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Abstract Background Oculocutaneous albinism type1 (OCA1) is caused by the TYR gene's homozygous and compound heterozygous variants. TKFC gene variants cause triokinase & FMN cyclase deficiency syndrome with variable multisystemic disorders. Objectives To determine the potential disease-causing variants in two deceased patients presenting atypical OCA1 features by demonstrating three generations for a single family. The two deceased neonates had severe skeletal abnormalities and fatal hypertrophic cardiomyopathy. We also explored the potential mechanisms for the causative relationship between TKFC and multisystem disorders. Patients and methods Due to the new emerging symptoms that weren’t reported before with the TYR gene, the following methods were performed: Sanger sequencing for the TYR gene, followed by whole exome sequencing, co-segregation, and computational analyses. Results Extensive parental consanguinity was found, and consequently an autosomal recessive mode of inheritance was prioritized. Upon performing sequencing and segregation data, the following has been confirmed: positive co-segregation of nonsense homozygous NM_000372.5:c.346C > T p.(Arg116*) variant in TYR gene and multisystem disease-missense homozygous NM_015533.4:c.598G > A p.(Val200Ile) variant in TKFC gene in the two affected index patients who deceased due to hypertrophic cardiomyopathy. Using computational analysis, we found that c.598G > A p.(Val200Ile) pathogenicity has led to the failure of L2-K1 active site closure due to the potential differential fluctuation between valine and isoleucine residues. Subsequently, disruption of endogenous DHA phosphorylation was found. Two potential mechanisms exploring the causative relationship between TKFC gene and multisystem disorders have been suggested. Conclusions This study presented a first family with the co-existence of biallelic variants in TYR and TKFC genes associating severe skeletal abnormalities and lethal hypertrophic cardiomyopathy. Neither of these genes would have been pursued in the standard genetic counseling. Such discovery is paving the way for more efficient genetic counseling. Comparing TKFC results with literature data showed that our relevant expanded TKFC variant is the 3rd worldwide.

Abstract Background Oculocutaneous albinism (OCA) is a genetically heterogeneous condition that is associated with reduced or absent melanin pigment in the skin, hair, and eyes, resulting in reduced vision, high sensitivity to light, and rapid and uncontrolled eye movements. To date, seventeen genes have been associated with OCA including syndromic and non-syndromic forms of the condition. Methods Whole exome sequencing (WES) was performed to identify pathogenic variants in nine Pakistani families with OCA, with validation and segregation of candidate variants performed using Sanger sequencing. Furthermore, the pathogenicity of the identified variants was assessed using various in-silico tools and 3D protein structural analysis software. Results WES identified biallelic variants in three genes explaining the OCA in these families, including four variants in TYR, three in OCA2, and two in HPS1, including two novel variants c.667C > T: p.(Gln223*) in TYR, and c.2009 T > C: p.(Leu670Pro) in HPS1. Conclusions Overall, this study adds further knowledge of the genetic basis of OCA in Pakistani communities and facilitates improved management and counselling services for families suffering from severe genetic diseases in Pakistan.

Background: oculocutaneous albinism (OCA) is a hereditary impairment of skin, hair, and eye pigmentation. The most common form of albinism is autosomal recessive albinism, caused by mutations in the TYR gene, accounting for approximately 40–50% of all cases of the disease in European populations. Common hypomorphic variants in the TYR gene could lead to a mild form of albinism in a compound heterozygous state with a pathogenic variant. Methods: we examined by allele specific MLPA a cohort consisting of 118 unrelated patients with albinism and 10 parents of these patients. The control cohort consisted of 200 unexamined Russian residents. Results: the patients with albinism were divided into three groups: without pathogenic variants in the TYR gene—70 patients, with one pathogenic variant in the TYR gene—20 patients, and with two pathogenic variants in the TYR gene—28 patients. Among the 20 patients with a single heterozygous variant in the TYR gene, 15 patients had the c.575C>A p.(Ser192Tyr) variant, and 15 had the c.1205G>A p.(Arg402Gln) variant. Both the c.575C>A p.(Ser192Tyr) and c.1205G>A p.(Arg402Gln) variants were identified in 12 patients. In addition to the aforementioned variants, an intronic variant c.1185-6208A>G (rs147546939) was identified in seven patients. Conclusions: the frequencies and the number of alleles c.575A, c.1205A, and c.1185-6208G in different groups of patients and the control group were compared. In this study, we demonstrate that the complex alleles [c.575C>A p.(Ser192Tyr); c.1205G>A p.(Arg402Gln)] and [c.575C>A p.(Ser192Tyr); c.1185-6208A>G; c.1205G>A p.(Arg402Gln)] are associated with oculocutaneous albinism, which is consistent with findings from other researchers. [ABSTRACT FROM AUTHOR]

Background: Oculocutaneous albinism type1 (OCA1) is caused by the TYR gene's homozygous and compound heterozygous variants. TKFC gene variants cause triokinase & FMN cyclase deficiency syndrome with variable multisystemic disorders. Objectives: To determine the potential disease-causing variants in two deceased patients presenting atypical OCA1 features by demonstrating three generations for a single family. The two deceased neonates had severe skeletal abnormalities and fatal hypertrophic cardiomyopathy. We also explored the potential mechanisms for the causative relationship between TKFC and multisystem disorders. Patients and methods: Due to the new emerging symptoms that weren't reported before with the TYR gene, the following methods were performed: Sanger sequencing for the TYR gene, followed by whole exome sequencing, co-segregation, and computational analyses. Results: Extensive parental consanguinity was found, and consequently an autosomal recessive mode of inheritance was prioritized. Upon performing sequencing and segregation data, the following has been confirmed: positive co-segregation of nonsense homozygous NM_000372.5:c.346C > T p.(Arg116*) variant in TYR gene and multisystem disease-missense homozygous NM_015533.4:c.598G > A p.(Val200Ile) variant in TKFC gene in the two affected index patients who deceased due to hypertrophic cardiomyopathy. Using computational analysis, we found that c.598G > A p.(Val200Ile) pathogenicity has led to the failure of L2-K1 active site closure due to the potential differential fluctuation between valine and isoleucine residues. Subsequently, disruption of endogenous DHA phosphorylation was found. Two potential mechanisms exploring the causative relationship between TKFC gene and multisystem disorders have been suggested. Conclusions: This study presented a first family with the co-existence of biallelic variants in TYR and TKFC genes associating severe skeletal abnormalities and lethal hypertrophic cardiomyopathy. Neither of these genes would have been pursued in the standard genetic counseling. Such discovery is paving the way for more efficient genetic counseling. Comparing TKFC results with literature data showed that our relevant expanded TKFC variant is the 3rd worldwide. [ABSTRACT FROM AUTHOR]

Background: Oculocutaneous albinism (OCA) is a genetically heterogeneous condition that is associated with reduced or absent melanin pigment in the skin, hair, and eyes, resulting in reduced vision, high sensitivity to light, and rapid and uncontrolled eye movements. To date, seventeen genes have been associated with OCA including syndromic and non-syndromic forms of the condition. Methods: Whole exome sequencing (WES) was performed to identify pathogenic variants in nine Pakistani families with OCA, with validation and segregation of candidate variants performed using Sanger sequencing. Furthermore, the pathogenicity of the identified variants was assessed using various in-silico tools and 3D protein structural analysis software. Results: WES identified biallelic variants in three genes explaining the OCA in these families, including four variants in TYR, three in OCA2, and two in HPS1, including two novel variants c.667C > T: p.(Gln223*) in TYR, and c.2009 T > C: p.(Leu670Pro) in HPS1. Conclusions: Overall, this study adds further knowledge of the genetic basis of OCA in Pakistani communities and facilitates improved management and counselling services for families suffering from severe genetic diseases in Pakistan. [ABSTRACT FROM AUTHOR]

Abstract Aim of the present study is to evaluate the relationship between genetic and phenotypic data in a series of patients affected by grade I and II of foveal hypoplasia with stable fixation and good visual acuity using multimodal imaging techniques. All patients underwent complete clinical and instrumental assessment including structural Optical Coherence Tomography (OCT), OCT Angiography and Adaptive Optics (AO) imaging. Central macular thickness (CMT), inner nuclear layer (INL), vessel density in superficial capillary plexus were the main variables evaluated with OCT technology. Cone density, cone spacing, cone regularity, cone dispersion and angular density were the parameters evaluated with AO. Genetic evaluation and trio exome sequencing were performed in all affected individuals. Eight patients (3 males and 5 females) with a mean age of 12.62 years (range 8–18) were enrolled. The mean best corrected visual acuity (BCVA) was 0.18 ± 0.13 logMAR, mean CMT was 291.9 ± 16.6 µm and INL was 26.2 ± 4.6 µm. The absence of a foveal avascular zone (FAZ) was documented by examination of OCT-A in seven patients in the superficial capillary plexus. However, there was a partial FAZ in the deep plexus in patients P5 and P8. Of note, all the patients presented with major retinal vessels clearly crossing the foveal center. All individuals exhibited a grade I or II of foveal hypoplasia. In 5 patients molecular analyses showed an extremely mild form of albinism caused by compound heterozygosity of a TYR pathogenic variant and the hypomorphic p.[Ser192Tyr;Arg402Gln] haplotype. One patient had Waardenburg syndrome type 2A caused by a de novo variant in MITF. Two patients had inconclusive molecular analyses. All the patients displayed abnormalities on OCT-A. Photoreceptor count did not differ from normal subjects according to the current literature, but qualitative analysis of AO imaging showed distinctive features likely related to an abnormal pigment distribution in this subset of individuals. In patients with foveal hypoplasia, genetic and multimodal imaging data, including AO findings, can help understand the physiopathology of the foveal hypoplasia phenotype. This study confirms that cone density and visual function can both be preserved despite the absence of a pit.

Background: Oculocutaneous albinism (OCA) is a congenital heterogeneous group of autosomal recessive disorders characterized by the absence or loss of melanin in the skin, eyes and hair of the affected individuals. Based on the mutated gene, OCA has been classified into eight sub-types (OCA1-8) with overlapping clinical phenotypes. Mutations in the TYR gene cause OCA1, the most prevalent OCA worldwide including India. Mutations in OCA2 and SLC45A2, both of which regulate melanosomal pH that is critical to TYR activity, cause OCA2 and OCA4 respectively, the other common OCA subtypes in India. Methods: In the present study, we have included 54 OCA-affected cases from 41 unrelated families representing 16 different marriage/ethnic groups from 17 districts of West Bengal, India. We pursued a PCR-sequencing based approach followed by bioinformatic analysis to identify mutations in TYR, OCA2 and SLC45A2 genes. Results: Mutations were detected in 27 of the 54 (50%) OCA patients from 18 unrelated families, representing 9 different marriage/ethnic groups from 11 districts of West Bengal. Three TYR variants: NM_000372.4: c.391 A > G, NP_000363.1: p. Lys131Glu; NM_000372.4: c.1037G > T; NP_000363.1: p. Gly346Val, NM_000372.4: c.715 C > T; NP_000363.1:p.Arg239Trp was identified for the first time in Eastern Indian OCA cases. A novel nonsense variant: NM_016180.5: c.389 T > A, NP_057264.4: p. Leu130* and a novel synonymous variation NM_016180.5: c.1092 A > G; NP_057264.4: p.364E = were identified in SLC45A2. Additionally, NM_016180.5: c.904A > T; NP_057264.4: p. Thre302Ser was identified for the first time in any Eastern Indian OCA case. We identified 2 previously reported mutations in OCA2. In concordance with previous reports, NM_000372.4: c.832C > T, NP_000363.1: p. (Arg278*) was the commonest TYR mutation. Conclusion: The results of our study enrich the mutational spectrum of the known OCA causing genes in Eastern India, which would facilitate accurate diagnosis, familial screening, carrier detection and containment of the disease load. [ABSTRACT FROM AUTHOR]

Prolonged exposure to environmental oxidative stress can result in visible signs of skin aging such as wrinkles, hyperpigmentation, and thinning of the skin. Oryza sativa variety Sang 5 CMU, an inbred rice cultivar from northern Thailand, contains phenolic and flavonoid compounds in its bran and husk portions that are known for their natural antioxidant properties. In this study, we evaluated the cosmetic properties of crude extracts from rice bran and husk of Sang 5 CMU, focusing on antioxidant, anti-inflammatory, anti-melanogenesis, and collagen-regulating properties. Our findings suggest that both extracts possess antioxidant potential against DPPH, ABTS radicals, and metal ions. Additionally, they could downregulate TBARS levels from 125% to 100% of the control, approximately, while increasing the expression of genes related to the NRF2-mediated antioxidant pathway, such as NRF2 and HO-1, in H2O2-induced human fibroblast cells. Notably, rice bran and husk extracts could increase mRNA levels of HO-1 more greatly than the standard L-ascorbic acid, by about 1.29 and 1.07 times, respectively. Furthermore, the crude extracts exhibited anti-inflammatory activity by suppressing nitric oxide production in both mouse macrophage and human fibroblast cells. Specifically, the bran and husk extracts inhibited the gene expression of the inflammatory cytokine IL-6 in LPS-induced inflammation in fibroblasts. Moreover, both extracts demonstrated potential for inhibiting melanin production and intracellular tyrosinase activity in human melanoma cells by decreasing the expression of the transcription factor MITF and the pigmentary genes TYR, TRP-1, and DCT. They also exhibit collagen-stimulating effects by reducing MMP-2 expression in H2O2-induced fibroblasts from 135% to 80% of the control, approximately, and increasing the gene associated with type I collagen production, COL1A1. Overall, the rice bran and husk extracts of Sang 5 CMU showed promise as effective natural ingredients for cosmetic applications. [ABSTRACT FROM AUTHOR]

Purpose: To present a case of molecularly confirmed oculocutaneous albinism (OCA) and retinitis pigmentosa (RP). Observations: A 46-year-old male with a lifelong established diagnosis of OCA and baseline best corrected visual acuity (BCVA) of 20/200, presented for worsening visual acuity over the last few years. BCVA was light perception and hand motion at face for the right and left eye, respectively. Fundus exam showed hypopigmented fundi with visible choroidal vessels and blunted foveal reflexes in both eyes. Optical coherence tomography showed foveal hypoplasia and outer retinal degenerative changes not typical of OCA. Fundus autofluorescence (FAF) imaging showed focal areas of decreased signal at the fovea, similar to areas of atrophy in an age matched patient with PDE6A-RP. Genetic testing identified a homozygous disease-causing variant in TYR c.1467dup, p. (Ala490Cysfs*20) causing OCA, and a homozygous pathogenic variant c.304C > A, p. (Arg102Ser) in PDE6A causing autosomal recessive RP. Conclusions and importance: This is the first report of a patient with OCA and RP. The lack of pigmentary changes can make the diagnosis of RP challenging in patients with albinism. FAF can show features suggestive of RP and genetic testing can establish the diagnosis. The findings described herein may help physicians diagnose an extremely rare phenotype.

【Objective】The shank and feather color, as the characteristic traits of breeds, which remains an important selective trait in the breeding process of new varieties. This study attempts to analyze the formation mechanism of green shank and white feather through molecular biology techniques and establish a molecular marker-assisted selection scheme for the above traits.【Method】The BCO2 gene was selected as the candidate gene for the formation of green and yellow shank, and the target site on the BCO2 was typed by sequencing to analyze the relationship between the locus and different traits. The MC1R, PMEL17 and TYR encoding extended locus e, dominant white I and recessive white C were used as candidate genes related to white feather, and the recessive white Plymouth Rock breeds, fast-and-big-type white-feather broiler, synthetic recessive white line and hybrid offspring white feather individuals were used as experimental materials. The relevant candidate mutations were genotyped by Sanger sequencing, and the relationship between the polymorphism of related genes and traits was analyzed.【Result】(1) The green and yellow shank trait is the result of the interaction of melanin in the dermis and the yellow scale in the shank. Mutations in the BCO2 gene are key to the formation of trait of green and yellow shank. The mutations site in 342 bp can be used for molecular marker-assisted selection of correlated traits. Purification can be achieved by eliminating CT genotype individuals. (2) The recessive white gene locus of synthetic recessive white line is cc, which is caused by a nonrecessive white mutation in the offspring white feathers. (3) The hybrids white feather offspring all carry the dominant white allele I encoded by the PMEL17 gene, all of which are heterozygous genotype Ii. (4) The hybrid white feather offspring all carry the E and ER alleles encoded by the MC1R gene. (5) The dominant white mutant alleles I, E and ER alleles are all derived from fast-and-big-type white-feather broiler.【Conclusion】The green shank trait is caused by a mutation in the BCO2 gene that controls the skin color. The SNP located at 342 bp of the amplified fragment can be used for molecular marker-assisted selection for this trait. The formation of white feather has no relation with recessive white mutation, which is mainly due to PMEL17 mutations encoding dominant white allele I.

Background: oculocutaneous albinism (OCA) is a hereditary impairment of skin, hair, and eye pigmentation. The most common form of albinism is autosomal recessive albinism, caused by mutations in the TYR gene, accounting for approximately 40–50% of all cases of the disease in European populations. Common hypomorphic variants in the TYR gene could lead to a mild form of albinism in a compound heterozygous state with a pathogenic variant. Methods: we examined by allele specific MLPA a cohort consisting of 118 unrelated patients with albinism and 10 parents of these patients. The control cohort consisted of 200 unexamined Russian residents. Results: the patients with albinism were divided into three groups: without pathogenic variants in the TYR gene—70 patients, with one pathogenic variant in the TYR gene—20 patients, and with two pathogenic variants in the TYR gene—28 patients. Among the 20 patients with a single heterozygous variant in the TYR gene, 15 patients had the c.575C>A p.(Ser192Tyr) variant, and 15 had the c.1205G>A p.(Arg402Gln) variant. Both the c.575C>A p.(Ser192Tyr) and c.1205G>A p.(Arg402Gln) variants were identified in 12 patients. In addition to the aforementioned variants, an intronic variant c.1185-6208A>G (rs147546939) was identified in seven patients. Conclusions: the frequencies and the number of alleles c.575A, c.1205A, and c.1185-6208G in different groups of patients and the control group were compared. In this study, we demonstrate that the complex alleles [c.575C>A p.(Ser192Tyr); c.1205G>A p.(Arg402Gln)] and [c.575C>A p.(Ser192Tyr); c.1185-6208A>G; c.1205G>A p.(Arg402Gln)] are associated with oculocutaneous albinism, which is consistent with findings from other researchers.

ABSTRACT: Beak color in ducks is a primary characteristic of local breeds and genetic resources. Among them, black beaks, a rare packaging trait of high-quality duck products, have attracted much attention. In this study, Runzhou White Created ducks (black beak) and white-feathered Putian black ducks (yellow beak) were used to construct the F2 generation resource population to study the changing discipline of beak color combined with the beak color statistics of gray-beaked ducklings of Runzhou White Created ducks. Subsequently, transcriptome sequencing was performed to identify genetic markers related to beak color. To explore the rules of beak color change and its regulatory network, trends, and trend analysis and weighted gene co-expression network analysis（WGCNA）were performed. The screening results were verified by real-time quantitative polymerase chain reaction. A large difference was observed between the beak colors of birds from the F1 generation at 0 and 42 d of age. The F2 generation results show that nearly half of the black-beaked ducklings become green-beaked; the proportion of black spots for gray- and patterned-beaked ducklings increases with age, with most becoming green-beaked. Moreover, the beak color darkened from the first day, and the gray color value decreased significantly from the second day. Transcriptome sequencing indicated that TYR was differentially expressed between black and yellow beaks at 4 to 6 wk of age, and trend and WGCNA analyses showed that EDNRB signaling pathway genes and MITF were highly expressed in the first week, and TYR, TYRP1, and DCT were highly expressed at 4 to 6 wk of age. Therefore, there is melanin synthesis and deposition after hatching for gray- and patterned-beaked ducklings, while the yellow pigment might be deposited in the epidermis of beaks for black-beaked ducklings. The EDNRB signaling pathway is probably involved in early melanosome maturation and melanin formation in duck beaks, and genes such as TYR can maintain the black-beak phenotype.

Oculocutaneous albinism (OCA) is a genetically heterogeneous disease and is most inherited in an autosomal recessive manner. The characteristic manifestation of OCA is due to disfunction of melanin synthesis. OCA1 is the most severe subtype of OCA and is caused by homozygous or compound heterozygous variants in tyrosinase (TYR) gene, which is the key gene for melanin synthesis. This study aimed to identify the genetic variants of a northern Chinese family with OCA1. Clinical information and peripheral blood samples were collected. PCR amplification and Sanger sequencing were used to detect the entire exons and adjacent flanking sequences of TYR gene. Functional prediction of variants was performed by various bioinformatic analyses, while the pathogenicity classification of variants was evaluated according to ACMG standards and guidelines. A missense variant NM_000372.5:c.107G > C;NP_000363.1:p.C36S was discovered in TYR gene which converted cysteine to serine. Another variant in intron, NM_000372.5:c.1037–7 T > A, also affected the function of TYR gene. We verified the pathogenicity of the intron variant with a pCAS2 mini‐gene based splicing assay and found that c.1037–7 T > A led to an insertion of 5 bp upstream from the common acceptor site of exon 3, which caused a frameshift TYR:c.1037–7 T > A:p.G346Efs*11. The results showed that the compound heterozygous variants c.107G > C:p.C36S and c.1037–7 T > A:p.G346Efs*11 of TYR gene were the pathogenic variants for this OCA1 family. [ABSTRACT FROM AUTHOR]

【Objective】The shank and feather color, as the characteristic traits of breeds, which remains an important selective trait in the breeding process of new varieties. This study attempts to analyze the formation mechanism of green shank and white feather through molecular biology techniques and establish a molecular marker-assisted selection scheme for the above traits. 【Method】The BCO2 gene was selected as the candidate gene for the formation of green and yellow shank, and the target site on the BCO2 was typed by sequencing to analyze the relationship between the locus and different traits. The MC1R, PMEL17 and TYR encoding extended locus e, dominant white I and recessive white C were used as candidate genes related to white feather, and the recessive white Plymouth Rock breeds, fast-and-big-type white-feather broiler, synthetic recessive white line and hybrid offspring white feather individuals were used as experimental materials. The relevant candidate mutations were genotyped by Sanger sequencing, and the relationship between the polymorphism of related genes and traits was analyzed. 【Result】 The green and yellow shank trait is the result of the interaction of melanin in the dermis and the yellow scale in the shank. Mutations in the BCO2 gene are key to the formation of trait of green and yellow shank. The mutations site in 342 bp can be used for molecular marker-assisted selection of correlated traits. Purification can be achieved by eliminating CT genotype individuals. The recessive white gene locus of synthetic recessive white line is cc, which is caused by a nonrecessive white mutation in the offspring white feathers. The hybrids white feather offspring all carry the dominant white allele I encoded by the PMEL17 gene, all of which are heterozygous genotype Ii. The hybrid white feather offspring all carry the E and ER alleles encoded by the MC1R gene. The dominant white mutant alleles I, E and ER alleles are all derived from fast-and-big-type white-feather broiler. 【Conclusion】The green shank trait is caused by a mutation in the BCO2 gene that controls the skin color. The SNP located at 342 bp of the amplified fragment can be used for molecular marker-assisted selection for this trait. The formation of white feather has no relation with recessive white mutation, which is mainly due to PMEL17 mutations encoding dominant white allele I. [ABSTRACT FROM AUTHOR]

Nonhuman primates (NHPs) are vital translational research models due to their high genetic, physiological, and anatomical homology with humans. The "golden" rhesus macaque (Macaca mulatta) phenotype is a naturally occurring, inherited trait with a visually distinct pigmentation pattern resulting in light blonde colored fur. Retinal imaging also reveals consistent hypopigmentation and occasional foveal hypoplasia. Here, we describe the use of genome-wide association in 2 distinct NHP populations to identify candidate variants in genes linked to the golden phenotype. Two missense variants were identified in the Tyrosinase-related protein 1 gene (Asp343Gly and Leu415Pro) that segregate with the phenotype. An additional and distinct association was also found with a Tyrosinase variant (His256Gln), indicating the light-colored fur phenotype can result from multiple genetic mechanisms. The implicated genes are related through their contribution to the melanogenesis pathway. Variants in these 2 genes are known to cause pigmentation phenotypes in other species and to be associated with oculocutaneous albinism in humans. The novel associations presented in this study will permit further investigations into the role these proteins and variants play in the melanogenesis pathway and model the effects of genetic hypopigmentation and altered melanogenesis in a naturally occurring nonhuman primate model. [ABSTRACT FROM AUTHOR]

However, because a subset of AT/RT-MYC may express SOX11, IHC MYC has to be negative in the face of SOX11 positivity to suggest an AT/RT-SHH. Atypical Teratoid/Rhabdoid Tumors (AT/RT) are malignant pediatric tumors of the Central Nervous System (CNS) and are molecularly characterized by a biallelic alteration of the I SMARCB1 i (95%) or I SMARCA4 i (5%) genes [[1]]. Of note, RNA-sequencing analysis was available for five of these cases, which, consistently with IHC, all clustered with the AT/RT-MYC tumors (Fig. AT/RT, DNA-methylation profiling, TYR, SHH, MYC, Immunohistochemistry. [Extracted from the article]

(1) Background: Poor palatability, large volume, and lack of variety of some liquid and powdered protein substitutes (PSs) for patients with phenylketonuria (PKU) and tyrosinemia (TYR) can result in poor adherence. This study aimed to evaluate a new unflavoured, powdered GMP-based PS designed to be mixed into drinks, foods, or with other PSs, in patients with PKU and TYR. (2) Methods: Paediatric and adult community-based patients were recruited from eight metabolic centres and prescribed ≥1 sachet/day (10 g protein equivalent (PE)) of the Mix-In-style PS over 28 days. Adherence, palatability, GI tolerance, and metabolic control were recorded at baseline and follow-up. Patients who completed at least 7 days of intervention were included in the final analysis. (3) Results: Eighteen patients (3–45 years, nine males) with PKU (n = 12) and TYR (n = 6) used the Mix-In-style PS for ≥7 days (mean 26.4 days (SD 4.6), range 11–28 days) alongside their previous PS, with a mean intake of 16.7 g (SD 7.7) PE/day. Adherence was 86% (SD 25), and GI tolerance was stable, with n = 14 experiencing no/no new symptoms and n = 3 showing improved symptoms compared to baseline. Overall palatability was rated satisfactory by 78% of patients, who successfully used the Mix-In-style PS in various foods and drinks, including smoothies, squash, and milk alternatives, as a top-up to meet their protein needs. There was no concern regarding safety/metabolic control during the intervention. (4) Conclusions: The 'Mix-In'-style PS was well adhered to, accepted, and tolerated. Collectively, these data show that providing a flexible, convenient, and novel format of PS can help with adherence and meet patients' protein needs. [ABSTRACT FROM AUTHOR]

Simple Summary: The research aims to investigate familial melanoma, a form of skin cancer that has a genetic predisposition. Melanoma is a dangerous cancer with a high potential for metastasis, and early detection is crucial for reducing its impact on patients. The study focuses on identifying specific genetic mutations associated with familial melanoma and correlating them with distinct dermoscopic patterns. By understanding the relationship between genetic mutations and dermoscopic features, the researchers aim to develop reference models to aid clinicians in identifying high-risk patients and their families. Establishing these correlations could lead to improved screening and a timely detection of new tumors in individuals with a family history of melanoma. Cutaneous melanoma is a highly aggressive skin cancer. It is estimated that 5% to 10% of the underlying mutations are hereditary and responsible for familial (or hereditary) melanoma. These patients are prone to the early development and higher risk of multiple melanomas. In recent years, an increasing number of genes have been identified thanks to genetic testing, allowing the subsequent surveillance of individuals at risk, yet it is still difficult to predict the presence of these mutations on a clinical basis. In this scenario, specific phenotypic and dermoscopic features could help clinicians in their identification. The aim of this work has been to correlate mutations to prevalent dermoscopic patterns, paving the way for reference models useful in clinical practice. In our cohort, out of 115 patients referred to genetic counseling for melanoma, 25 tested positive (21.7%) for critical mutations: CDKN2A (n = 12), MITF (n = 3), BAP1 (n = 1), MC1R (n = 3), PTEN (n = 1), TYR (n = 2), OCA2 (n = 1), and SLC45A2 (n = 2). The phenotype profiles obtained through the digital acquisition, analysis, and description of both benign and malignant pigmented lesions showed a predominance of the type II skin phenotype, with an elevated mean total nevus number (182 moles, range 75–390). As for dermoscopic features, specific mutation-related patterns were described in terms of pigmentation, areas of regression, and vascular structures. Although further studies with larger cohorts are needed, our work represents the beginning of a new approach to the study and diagnosis of familial melanoma, underlining the importance of clinical and dermoscopic patterns, which may constitute a reference model for each gene, enabling comparison. [ABSTRACT FROM AUTHOR]

Without affecting cell viability, epigallocatechin gallate (EGCG), gallocatechin gallate (GCG), theaflavine-3,3′-digallate (TFDG), or theasinensin A (TSA) have been found to effectively reduce intracellular melanin content and tyrosinase (TYR) activity. However, studies on the anti-melanogenic mechanism of the above samples remain weak, and the activities of these samples in regulating melanogenesis at the molecular level lack comparison. Using B16F10 cells with the α-melanocyte-stimulating hormone (α-MSH) stimulation and without the α-MSH stimulation as models, the effects of EGCG, GCG, TFDG, or TSA on cell phenotypes and expression of key targets related to melanogenesis were studied. The results showed that α-MSH always promoted melanogenesis with or without adding the four samples. Meanwhile, the anti-melanogenic activities of the four samples were not affected by whether the α-MSH was added in the medium or not and the added time of the α-MSH. On this basis, the 100 µg/mL EGCG, GCG, TFDG, or TSA did not affect the TYR catalytic activity but inhibited melanin formation partly through downregulating the melanocortin 1 receptor (MC1R), microphthalmia-associated transcription factor (MITF), and the TYR family. The downregulation abilities of catechins on the TYR family and MITF expression were stronger than those of dimers at both the transcription and translation levels, while the ability of dimers to downregulate the MC1R expression was stronger than that of catechins at both the transcription and translation levels to some extent. The results of molecular docking showed that these four samples could stably bind to MC1R protein. Taken together, this study offered molecular mechanisms for the anti-melanogenic activity of the EGCG, GCG, TFDG, and TSA, as potential effective components against the UV-induced tanning reactions, and a key target (MC1R) was identified. [ABSTRACT FROM AUTHOR]

Foxj2(Forkhead Box J2) gene, a member of the forkhead box transcription protein family, is positively correlated with the expression of epithelial-cadherin(E-cadherin, CDH1) in U87 cells and U251 cells, and CDH1 involved melanogenesis has a role in mediating the integrity of the epidermal-melanin unit. In order to verify that Foxj2 gene is involved in regulating melanogenesis in alpaca melanocytes, in this study, PCR method was used to verify the expression of Foxj2 gene in alpaca skin, the correlation between Foxj2 and melanogenesis related gene TYR, and Foxj2 and melanogenesis related proteins was analyzed by bioinformatics. Foxj2 siRNA and empty siRNA were synthesized, alpaca melanocyte model of silencing siRNA was constructed, and the transfection of cells was observed and recorded. Real-Time-PCR was used to detect the mRNA changes of Foxj2 gene and melanogenesis related gene TYR in the alpaca melanocytes of each group. Western blot was used to detect and compare the changes of Foxj2 and TYR protein levels in each group cell. Three kinds of melanin(total melanin, eumelanin, brown melanin) in the cells of each group were purified, and a microplate reader was used to measure the OD value of the three kinds of melanin in the cells of each group and compare changes. The results showed that Foxj2 gene expression was detected in alpaca melanocytes. Bioinformatics analysis showed that Foxj2 gene was involved in a series of functions such as amino acid transport regulation, growth factor and so on. The Forkhead domain existing in Foxj2 could have binding sites with the TYR gene promoter. Real-Time PCR results showed that compared with the NC group, the mRNA expression of Foxj2 in the silence group was extremely significantly decreased by 24 990%, and the expression of TYR was significantly increased by 35%. Western-blot results showed that the protein relative expression level of Foxj2 gene in the silence group extremely significantly decreased by 25%, and the protein relative expression level of TYR extremely significantly increased by 25%. The wavelength analysis of microplate reader showed that compared with the NC group, the total melanin relative expression levels of the silence group significantly increased by 88.0%, the eumelanin relative expression levels extremely significantly increased by 21.8%, and the pheomelanin relative expression level extremely significantly increased by 21.6%. Inhibiting the transcription of Foxj2 gene in alpaca melanocytes could increase melanogenesis in alpaca melanocytes, and play a role in promoting the main regulatory gene TYR of melanogenesis, proving that Foxj2 gene may play a regulatory role in melanogenesis in alpaca melanocytes. [ABSTRACT FROM AUTHOR]

UVB exposure accelerates skin aging and pigmentation. Melatonin effectively regulates tyrosinase (TYR) activity and aging. The purpose of this study was to determine the association between premature senescence and pigmentation, and the mechanism of melanin synthesis effected by melatonin. Primary melanocytes were extracted and identified from the male foreskin. To inhibit TYR expression, primary melanocytes were transduced with the lentivirus pLKD-CMV-EGFP-2A-Puro-U6-TYR. The wild-type TYR(+/+) and TYR(–/–) or TYR(+/–) knockout C57BL/6 J mice were used to determine the role of TYR on melanin synthesis in vivo. Results showed that UVB-induced melanin synthesis is dependent on TYR in primary melanocytes and mice. Furthermore, in primary melanocytes pretreated with Nutlin-3 or PFT-α to up or downregulate p53, results showed that premature senescence and melanin synthesis increased in primary melanocytes after UVB irradiation at 80 mJ/cm2, and further increased after being treated with Nutlin-3, while significantly decreased with PFT-α. In addition, melatonin inhibited UVB-induced premature senescence associated with inactivation of p53 and phosphorylation of p53 on Ser15 (ser-15), a decrease of melanin synthesis accompanied by reduced TYR expression. Moreover, skin erythema and pigmentation induced by UVB were reduced in the dorsal and ear skin of mice topically pretreated with 2.5% melatonin. These indicate that melatonin inhibits UVB-induced senescence-associated pigmentation via the p53-TYR pathway in primary melanocytes and prevents pigmentation obviously in the dorsal and ear skin of C57BL/6 J mice after UVB irradiation. Key messages: P53 links UVB irradiation-induced senescence and senescence-associated pigmentation and regulates TYR in primary melanocytes after UVB irradiation. Melatonin inhibits senescence-associated pigmentation through the p53-TYR pathway in primary melanocytes. Melatonin prevents skin erythema and melanin pigmentation induced by UVB irradiation in the dorsal and ear skin of C57BL/6J mice. [ABSTRACT FROM AUTHOR]

• The TYR variants were affected in protein expression with almost abolishing tyrosinase activity. • Variants affected TYR N-glycan processing that failed to enter the Golgi apparatus and instead remained in the ER. • The TYR variants may induce endoplasmic reticulum stress and trigger degradation through the ERLAD pathway. Oculocutaneous albinism (OCA) is a genetically heterogeneous group of autosomal recessive disorders, which presents with decreased or absent pigmentation in the hair, skin, and eyes. OCA1, as a subtype of OCA, is caused by mutations in the tyrosinase gene (TYR). In this study, we performed in vitro functional analysis of eight TYR variants (one frameshift variant: c.929dupC (p.Arg311Lysfs*7); seven missense variants: c.896G>A (p.Arg299His), c.1234C>A (p.Pro412Thr), c.1169A>G (p.His390Arg), c.937C>A (p.Pro313Thr), c.636A>T (p.Arg212Ser), c.623 T>G (p.Leu208Arg), c.1325C>A (p.Ser442Tyr)) identified in Chinese OCA families. TYR plasmids were transfected into HEK 293 T cells to explore the effects of TYR variants on their processing, protein expression, activity, and degradation. The results showed that all eight variants caused TYR to be retained in the endoplasmic reticulum (ER), processing was blocked, and TYR activity almost disappeared; the frameshift variant caused the size of the TYR protein to be reduced by about 30KD, and the protein expression of the remaining seven missense variants was reduced; the ER-associated degradation (ERAD) pathway mediates the degradation of TYR variants that occur on the Tyrosinase copper-binding domain, while the degradation of TYR variants that are not located on that domain may be mediated by a new degradation pathway——ER-to-lysosome-associated degradation (ERLAD). In summary, TYR variants affected their protein processing and activity, and may also induce ER stress and trigger degradation through the ERLAD pathway in addition to the ERAD degradation pathway, providing new insights into the potential pathogenic mechanism for OCA1 caused by TYR variants. [ABSTRACT FROM AUTHOR]

Abstract Background Oculocutaneous albinism (OCA) is a group of heterogeneous genetic diseases characterized by a reduction or complete lack of pigmentation in the hair, skin, and eyes. It is associated with reduced visual acuity, nystagmus, photophobia, and strabismus. OCA type 1 (OCA1) and type 2 (OCA2) are caused by mutations in the tyrosinase (TYR) and OCA2 genes, which are responsible for most cases of OCA. The present study aimed to identify the mutational spectra of 18 southwest Chinese probands with OCA. Results We used a skin disease-targeted panel to sequence more than 400 genes, including 23 genes (TYR, OCA2, AP3B1, BLOC1S3, BLOC1S6, C10orf11, DTNBP1, FRMD7, GPR143, HPS1, HPS3, HPS4, HPS5, HPS6, LYST, MC1R, MITF, MLPH, MYO5A, RAB27A, SLC24A5, SLC45A2, TYRP1) associated with syndromic and non-syndromic albinism. The targeted panel was applied to 18 patients from southwest China, nine (50%) patients were diagnosed with OCA1, and nine (50%) were diagnosed with OCA2. Our data indicate that OCA1 and OCA2, the most common subtypes, probably have the same prevalence in southwest China. In total, we identified 26 variants in TYR and OCA2 from 18 OCA cases using the NGS technology, including 24 variants presented in the Human Gene Mutation Database Professional (HGMD) and two novel variants, c.559_560insCATTATTATGTGTCAAATTATCCCC in TYR and c.1514 T > C in OCA2, which have not been previously reported. According to the American College of Medical Genetics and Genomics (ACMG) classification, c.559_560insCATTATTATGTGTCAAATTATCCCC (p.G190Cfs*12) is classified as a pathogenic variant, and c.1514 T > C (p.F505S) is evaluated as a likely pathogenic variant. Conclusions Two novel variants were identified which will expand the mutational spectra of TYR and OCA2. The results of the present study may have implications for genetic counseling, carrier screening, and clinical management of the disease.

Objective: The TYR (Tyrosinase) and MC1R (Melanocortin 1 receptor) genes are recognized as important genes involved in plumage pigmentation in Korean native chickens. Specifically, most color patterns in chicken result from differential expression of the TYR gene. In this study, the co-segregation of the pigmentation and sequence of the TYR and MC1R genes was investigated through intercrosses between red (R1q1), red with black and black plumage color types of native Korean chickens. Materials and Methods: Using DNA, RNA, and tissue by plumage color of each Korean native chickens, the role of major genes in pigmentation of pheomelanin was evaluated. Reverse tran¬scription polymerase chain reaction, sequencing, western blot, and immunohistochemical were performed to determine the effect of TYR and MC1R genes on plumage pigmentation in Korean native chickens. Results: The KCO line (Korean chicken Ogol: Black-line) with an EEC _ genotype exhibited black feathers, whereas red and red mixed with black chicken with EeC genotype exhibited white feathers. There were notable differences between the base sequences of MC1R and TYR in three Korean chicken breeds, with the highest variation in TYR. Perhaps this is the key characteristics of Korean chicken. Further, we analyzed the expression patterns of MC1R and TYR genes in each type of Korea native chicken and observed that TYR expression was high in feather follicle (R1q2) of KCO tissue. However, native red (Korean chicken red) and native red with black (Korean chicken red dark) chickens have increased TYR expression in the tissue. However, the expression of MC1R was much different from that of TYR. Conclusion: In this study, our results suggest that the differences in position and TYR expres¬sion levels exert more influence on plumage pigmentation in native Korean chicken breeds than changes in MC1R expression levels. [J Adv Vet Anim Res 2021; 8(2.000): 266-273]

OCA (oculocutaneous albinism) refers to a group of heterogeneous congenital disorders of which the common manifestations are variable degrees of cutaneous hypopigmentation and significant visual impairment, including poor visual acuity, photophobia, and nystagmus. Molecular analysis may elucidate its pathogenesis and be in favor of accurate diagnosis. High-throughput sequencing and Sanger sequencing were performed to detect mutational alleles and in silico analysis was performed for prediction of variant pathogenicity. Ten TYR-related and two OCA2-related patients were identified with 16 different variants with potential pathogenicity. Two novel missense variants [TYR: c.623T > G, p(Leu208Arg) and OCA2: c.1325A > G, p(Asn442Ser)] are identified in this study, and three OCA cases are reported for the first time in Chinese population based on their associated variants. Analysis of crystal structures of TYR ortholog and its paralog TYRP1 suggests that the substitution of Leu208 may have an impact on protein stability. This study may facilitate OCA diagnosis by expanding the mutational spectrum of TYR and OCA2 as well as further basic studies about these two genes. [ABSTRACT FROM AUTHOR]

Oculocutaneous albinism is an autosomal recessive disorder characterized by the presence of typical ocular features, such as foveal hypoplasia, iris translucency, hypopigmented fundus oculi and reduced pigmentation of skin and hair. Albino patients can show significant clinical variability; some individuals can present with only mild depigmentation and subtle ocular changes. Here, we provide a retrospective review of the standardized clinical charts of patients firstly addressed for evaluation of foveal hypoplasia and slightly subnormal visual acuity, whose diagnosis of albinism was achieved only after extensive phenotypic and genotypic characterization. Our report corroborates the pathogenicity of the two common TYR polymorphisms p.(Arg402Gln) and p.(Ser192Tyr) when both are located in trans with a pathogenic TYR variant and aims to expand the phenotypic spectrum of albinism in order to increase the detection rate of the albino phenotype. Our data also suggest that isolated foveal hypoplasia should be considered a clinical sign instead of a definitive diagnosis of an isolated clinical entity, and we recommend deep phenotypic and molecular characterization in such patients to achieve a proper diagnosis. [ABSTRACT FROM AUTHOR]

To evaluate the effect of liquiritigenin on melanogenesis in mouse melanoma(B16F10)cells, and to explore its molecular mechanism. B16F10 cells were treated with different concentrations isoliquiritin(0, 10, 20, 40, 60, 80 μmol/L)for 48 hours, and methyl thiazolyl tetrazolium(MTT)assay was performed to evaluate changes in cellular proliferative activity. According to the cellular proliferation activity, 4 concentrations(0, 10, 20, 40 μmol/L)were screened out. Melanin content assay and Masson-Fontana ammoniacal silver staining were conducted to determine the melanin content in B16F10 cells. Western blot analysis was conducted to determine the protein expression of melanog-enesis related proteins TYR, TRP-1 and MITF, and MAPK signaling pathways. Compared with the control group, 20, 40 μmol/L liquiritigenin significantly promote melanogenesis and the expression of TYR, TRP-1, and MITF. Compared with the control group, 40 μmol/L liquiritigenin activate the p38 pathway in B16F10 cells. To further verify whether liquiritigenin promotes melanogenesis by activating the p38 pathway, B16F10 cells were pretreated with SB203580(the inhibitor of p38)for 1 h before liquiritigenin was applied for 48 h. SB203580 significantly reversed liquiritigenin-induced melanogenesis in B16F10 cells. Liquiritigenin significantly promotes melanogenesis. These functions can be ascribed to the activation of the p38 signaling pathway. Once this pathway was activated, it would increase the expression of TYR, TRP-1 and MITF, finally increasing the pigmentation. [ABSTRACT FROM AUTHOR]

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This study sought to analyse tyrosinase (TYR) pathogenic variants in a Chinese Mongolian family with progressive symmetric erythrokeratoderma (PSEK). We collected clinical data and peripheral blood DNA samples from the initial patient and his family members for polymerase chain reaction (PCR) amplification and whole-exome sequencing of the coding region of TYR. Genetic analysis showed a TYR insertion (c. 929_930insC; p.Arg311Lysfs*7) in the patient that was not detected in any of the normal family members or in 100 healthy controls. This report provides the first description of this TYR pathogenic variant (c. 929_930insC) in a family; functional studies and further research are needed for an in-depth analysis.

Background: Oculocutaneous albinism (OCA) is a group of heterogeneous genetic diseases characterized by a reduction or complete lack of pigmentation in the hair, skin, and eyes. It is associated with reduced visual acuity, nystagmus, photophobia, and strabismus. OCA type 1 (OCA1) and type 2 (OCA2) are caused by mutations in the tyrosinase (TYR) and OCA2 genes, which are responsible for most cases of OCA. The present study aimed to identify the mutational spectra of 18 southwest Chinese probands with OCA. Results: We used a skin disease-targeted panel to sequence more than 400 genes, including 23 genes (TYR, OCA2, AP3B1, BLOC1S3, BLOC1S6, C10orf11, DTNBP1, FRMD7, GPR143, HPS1, HPS3, HPS4, HPS5, HPS6, LYST, MC1R, MITF, MLPH, MYO5A, RAB27A, SLC24A5, SLC45A2, TYRP1) associated with syndromic and non-syndromic albinism. The targeted panel was applied to 18 patients from southwest China, nine (50%) patients were diagnosed with OCA1, and nine (50%) were diagnosed with OCA2. Our data indicate that OCA1 and OCA2, the most common subtypes, probably have the same prevalence in southwest China. In total, we identified 26 variants in TYR and OCA2 from 18 OCA cases using the NGS technology, including 24 variants presented in the Human Gene Mutation Database Professional (HGMD) and two novel variants, c.559_560insCATTATTATGTGTCAAATTATCCCC in TYR and c.1514 T > C in OCA2, which have not been previously reported. According to the American College of Medical Genetics and Genomics (ACMG) classification, c.559_560insCATTATTATGTGTCAAATTATCCCC (p.G190Cfs*12) is classified as a pathogenic variant, and c.1514 T > C (p.F505S) is evaluated as a likely pathogenic variant. Conclusions: Two novel variants were identified which will expand the mutational spectra of TYR and OCA2. The results of the present study may have implications for genetic counseling, carrier screening, and clinical management of the disease. [ABSTRACT FROM AUTHOR]

Albinism is a heterogeneous group of genetically determined diseases associated with complete or partial disruption of melanin synthesis. There are various forms of hereditary albinism, including oculocutaneous albinism, ocular albinism, and different syndromic forms. The study analyzed a sample of patients (n = 90) with varied forms of albinism for the presence of pathogenic variants of the nucleotide sequence in the TYR gene as the most common cause of type 1 oculocutaneous albinism (OCA1). This clinical and genetic form was found in 32 patients. On the basis of the results obtained, we examined the spectrum and frequency of variants in the TYR gene. Also, we described the clinical signs that are most common among patients, as well as clinical features atypical of this disease. [ABSTRACT FROM AUTHOR]

Oculocutaneous albinism (OCA) is associated with a wide range of clinical presentations and has been categorized with syndromic and non-syndromic features. The most common causative genes in non-syndromic OCA are TYR and OCA2 and HSP1 is in the syndromic albinism. The objective of this study was to identify pathogenic variants in congenital OCA families from Pakistan. Eight consanguineous families were recruited, and clinical and ophthalmological examination was carried out to diagnose the disease. Whole blood was collected from the participating individuals, and genomic DNA was extracted for sequencing analysis. TruSight one-panel sequencing was carried out on one affected individual of each family, and termination Sanger sequencing was carried out to establish the co-segregation of the causative gene or genes. In silico analysis was conducted to predict the causative pathogenic variants. Two families were found to have novel genetic pathogenic variants, and six families harbored previously reported variants. One novel compound heterozygous pathogenic variant in the TYR gene, c.1002delA; p.Ala335LeufsTer20, a novel frameshift deletion pathogenic variant and c.832C>T; and p.Arg278Ter (a known pathogenic variant) were found in one family, whereas HPS1; c.437G>A; and p.Trp146Ter were detected in another family. The identification of new and previous pathogenic variants in TYR, OCA2, and HPS1 genes are causative of congenital OCA, and these findings are expanding the heterogeneity of OCA. [ABSTRACT FROM AUTHOR]

The Italian Asinara donkey and the White Austro-Hungarian Baroque donkey share an identical coat colour phenotype which is characterised by unpigmented skin, white hair, white hooves and blue eyes. Whereas for the Asinara donkey the white coat colour phenotype was assigned to a recessive inherited missense mutation in the Tyrosinase gene (TYR), the underlying genetic background in the White Austro-Hungarian Baroque donkey has not been studied yet. Historical documents derived by the presence of Austro-Hungarian prisoners in the Asinara Island during the First World War might suggest a possible common origin of the same coat colour phenotype in the two breeds. Genotyping of this mutation in the TYR gene and the loci in the KIT gene associated with Dominant White and White Spotting phenotype, revealed, that none of the mutated alleles segregated in the White Austro-Hungarian Baroque Donkey breed. Also sequencing analysis of the TYR gene did not result in the detection of further candidate variants. Therefore, the TYR gene can be excluded as a possible candidate gene for this specific coat colour in the White Austro-Hungarian Baroque donkey. This result excludes a common genetic origin of the white coat colour of the Asinara and White Austro-Hungarian Baroque donkeys that historical documents could have suggested.Highlights Historical information indicated that the white (albino) Asinara donkey breed and the White Austro-Hungarian Baroque donkey breed could be genetically related. The TYR mutation identified in Asinara donkeys and known polymorphic sites in the KIT gene associated with depigmented white coat colour in donkeys do not segregate in the White Austro-Hungarian Baroque Donkey. Due to different underlying genetic background of one identical phenotype in two populations, no common ancestors can be assumed between Asinara donkey and White Austro-Hungarian Baroque donkey throughout the last century.

Abstract Background Advanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the genetic architecture of early AMD. Methods To identify genetic factors for early AMD, we conducted a genome-wide association study (GWAS) meta-analysis (14,034 cases, 91,214 controls, 11 sources of data including the International AMD Genomics Consortium, IAMDGC, and UK Biobank, UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and via an automated machine learning approach for > 170,000 photographs from UKBB. We searched for early AMD loci via GWAS and via a candidate approach based on 14 previously suggested early AMD variants. Results Altogether, we identified 10 independent loci with statistical significance for early AMD: (i) 8 from our GWAS with genome-wide significance (P

The reconstructed name of the early Germanic god *Wōdanaz is generally traced to a Proto-Indo-European root *u̯ā̆t- meaning 'spiritually aroused, possessed'. The signification contrasts sharply with the attributes of the primal Germanic sky and war god *Tīwaz, whose name references the bright sky. In a cultural development not yet fully explained, the former displaces the latter as the chief god. In this article, a homophone of the above PIE root, designated *u̯ā̆t- (2), and meaning 'to bow down, bend, stoop', is posited as the root of a theonym meaning 'the bent, stooped one'. He is identified as the Germanic psychopomp and lord of the dead with ties to an ancestor cult. From a largely quiescent role as the bowed or bent-knee god, he emerges from the underworld, when Germanic tribes resemanticized the reflex of the *u̯ā̆t- (2) root 'bent, bowed' – militarized it. The new chief god was understood as 'the master of battle rage', based on the prioritization of the signification inherent in the root *u̯ā̆t- (1). [ABSTRACT FROM AUTHOR]

Sexual dimorphism of feather color is typical in mallards, in which drakes exhibit green head feathers, while females show dull head feather color. We showed that more melanosomes deposited in the males' head's feather barbules than females and further form a two-dimensional hexagonal lattice, which conferred the green feather coloration of drakes. Additionally, transcriptome analysis revealed that some essential melanin biosynthesis genes were highly expressed in feather follicles during the development of green feathers, contributing to melanin deposition. We further identified 18 candidate differentially expressed genes, which may affect the sharp color differences between the males' head feathers, back feathers, and the females' head feathers. TYR and TYRP1 genes are associated with melanin biosynthesis directly. Their expressions in the males' head feather follicles were significantly higher than those in the back feather follicles and females' head feather follicles. Most clearly, the expression of TYRP1 was 256 and 32 times higher in the head follicles of males than in those of the female head and the male back, respectively. Hence, TYR and TYRP1 are probably the most critical candidate genes in DEGs. They may affect the sexual dimorphism of head feather color by cis -regulation of some transcription factors and the Z-chromosome dosage effect. [ABSTRACT FROM AUTHOR]

This study sought to analyse tyrosinase (TYR) pathogenic variants in a Chinese Mongolian family with progressive symmetric erythrokeratoderma (PSEK). We collected clinical data and peripheral blood DNA samples from the initial patient and his family members for polymerase chain reaction (PCR) amplification and whole-exome sequencing of the coding region of TYR. Genetic analysis showed a TYR insertion (c. 929_930insC; p.Arg311Lysfs*7) in the patient that was not detected in any of the normal family members or in 100 healthy controls. This report provides the first description of this TYR pathogenic variant (c. 929_930insC) in a family; functional studies and further research are needed for an in-depth analysis. [ABSTRACT FROM AUTHOR]

Sexual dimorphism of feather color is typical in mallards, in which drakes exhibit green head feathers, while females show dull head feather color. We showed that more melanosomes deposited in the males’ head’s feather barbules than females and further form a two-dimensional hexagonal lattice, which conferred the green feather coloration of drakes. Additionally, transcriptome analysis revealed that some essential melanin biosynthesis genes were highly expressed in feather follicles during the development of green feathers, contributing to melanin deposition. We further identified 18 candidate differentially expressed genes, which may affect the sharp color differences between the males’ head feathers, back feathers, and the females’ head feathers. TYR and TYRP1 genes are associated with melanin biosynthesis directly. Their expressions in the males’ head feather follicles were significantly higher than those in the back feather follicles and females’ head feather follicles. Most clearly, the expression of TYRP1 was 256 and 32 times higher in the head follicles of males than in those of the female head and the male back, respectively. Hence, TYR and TYRP1 are probably the most critical candidate genes in DEGs. They may affect the sexual dimorphism of head feather color by cis-regulation of some transcription factors and the Z-chromosome dosage effect.

The widely recognized color polymorphisms of molluscan shell have been appreciated for hundreds of years by collectors and scientists, while molecular mechanisms underlying shell pigmentation are still poorly understood. Tyrosinase is a key rate–limiting enzyme for the biosynthesis of melanin. Here, we performed an extensive multi-omics data mining and identified two tyrosinase genes, including tyrosinase and tyrosinase-like protein 2 (Tyr and Typ-2 respectively), in the Pacific oyster Crassostrea gigas, and investigated the expression patterns of tyrosinase during adults and embryogenesis in black and white shell color C. gigas. Tissue expression analysis showed that two tyrosinase genes were both specifically expressed in the mantle, and the expression levels of Tyr and Typ-2 in the edge mantle were significantly higher than that in the central mantle. Besides, Tyr and Typ-2 genes were black shell-specific compared with white shell oysters. In situ hybridization showed that strong signals for Tyr were detected in the inner surface of the outer fold, whereas positive signals for Typ-2 were mainly localized in the outer surface of the outer fold. In the embryos and larvae, the high expression of Tyr mRNA was detected in eyed-larvae, while Typ-2 mRNA was mainly expressed at the trochophore and early D-veliger. Furthermore, the tyrosinase activity in the edge mantle was significantly higher than that in the central mantle. These findings indicated that Tyr gene may be involved in shell pigmentation, and Typ-2 is more likely to play critical roles not only in the formation of shell prismatic layer but also in shell pigmentation. In particular, Typ-2 gene was likely to involve in the initial non-calcified shell of trochophores. The work provides valuable information for the molecular mechanism study of shell formation and pigmentation in C. gigas. [ABSTRACT FROM AUTHOR]

Abstract Background Oculocutaneous albinism (OCA) is a human autosomal-recessive hypopigmentation disorder with hypopigmentation in the skin, hair, and eyes. OCA1 and OCA2 are caused by mutations of the TYR and OCA2 genes, respectively, which are responsible for most oculocutaneous albinism. However, the incidence of oculocutaneous albinism patients in Guangxi remains unclear. Methods To evaluate the molecular basis of oculocutaneous albinism in thirty-six patients in Guangxi, China. Peripheral venous blood samples were collected from these unrelated patients. The TYR and OCA2 genes of all individuals were analyzed by direct DNA sequencing and the sequences compared with are reference database and bioinformatics analysis. Results Among the 36 OCA patients, 8(22.2%) were found mutations on TYR gene, 28 (77.8%) on OCA2. And we identified Twenty-seven different TYR and OCA2 mutations in these patients, including one novel TYR framshift mutation c.561_562insTTATTATGTGTCAAATTATCCCCCA, three novel OCA2 mutations: one nonsense mutation c.2195C > G(p.S732X), one deletation mutation(c.1139-1141delTGG), one missense mutations c.2495A > C(p.H832P). The population screening and the bioinformatic analysis to determined the effects of the mutations, which revealed these four novel mutations were pathogenic. Conclusions This study expands the mutation spectrum of oculocutaneous albinism. Four novel mutational alleles c.1139-1141delTGG, c.1832 T > C and c.2195C > G and of the OCA2 gene and c.561_562insTTATTATGTGTCAAATTATCCCCCA of TYR were associated with OCA. The genotype–phenotype correlations suggest that molecular diagnosis is more accurate and important in OCA.

Oculocutaneous albinism (OCA) is a genetic disorder characterized by skin, hair, and eye hypopigmentation due to a reduction or absence of melanin. Clinical manifestations include vision problems and a high susceptibility to skin cancer. In its non-syndromic form, OCA is associated with six genes and one chromosomal region. Because OCA subtypes are not always clinically distinguishable, molecular analysis has become an important tool for classifying types of OCA, which facilitates genetic counseling and can guide the development of new therapies. We studied eight Brazilian individuals aged 1.5–18 years old with clinical diagnosis of OCA. Assessment of ophthalmologic characteristics showed results consistent with albinism, including reduced visual acuity, nystagmus, and loss of stereoscopic vision. We also observed the appearance of the strabismus and changes in static refraction over a 2-year period. Dermatologic evaluation showed that no participants had preneoplastic skin lesions, despite half of the participants reporting insufficient knowledge about skin care in albinism. Whole-exome and Sanger sequencing revealed eight different mutations: six in the TYR gene and two in the SLC45A2 gene, of which one was novel and two were described in a population study but were not previously associated with the OCA phenotype. We performed two ophthalmological evaluations, 2 years apart; and one dermatological evaluation. To the best of our knowledge, this is the first study to perform clinical follow-up and genetic analysis of a Brazilian cohort with albinism. Here, we report three new OCA causing mutations.

Mridvika Narda, Gabriel Bauza, Palmira Valderas, Corinne Granger Innovation and Development, ISDIN SA, Barcelona, Spain Background: The effects of pollution on health have received increasing attention in recent years. Extrinsic skin aging occurs via multiple processes, and pollution is now recognized as a major component, causing increased pigmentation and wrinkles via oxidative mechanisms. We tested the antipollution efficacy of a cosmetic facial cream (FC) by assessing its effects on carbon particle adhesion to skin and on oxidative and inflammatory pathways in the skin. Methods: In an in vivo study, FC was applied once to the forearms of healthy subjects. Carbon E153 powder was applied, and the skin was washed under standardized conditions. Images were taken using a dermoscope to determine the area of particle adherence. Each participant served as their own control, with the contralateral forearm being untreated with the FC but otherwise following the same protocol. In a 5-day ex vivo study, skin explants were treated with the FC daily and exposed to vaporized pollutants on day 2 and day 4 via a closed system. Explants were sampled at baseline and day 5 and culture media on day 5. The parameters evaluated were cellular viability on microscopy, Nrf2 immunostaining, malondialdehyde (MDA) levels in culture, melanin levels, and gene expression profile (TYR, IL6, and CYP1A1). Results: In the in vivo adhesion study, after standardized washing, carbon particle deposition on skin treated with the FC was significantly lower than that on untreated skin. In the ex vivo study, samples treated with the FC had reduced Nrf2 staining and MDA levels vs polluted controls. Melanin did not change significantly. The FC modulated pollution-induced increases in CYP1A1, IL-6, and TYR. Conclusion: This FC reduces particle adhesion to skin after a single application and protects against pollution-induced oxidative and inflammatory pathways in the skin. Keywords: pollution, skin aging, shield, barrier, exopolysaccharide, genomic, Nrf2, TYR

To identify the mutational spectrum of 63 northwest Chinese probands with Oculocutaneous albinism (OCA), and identify correlations between phenotype and genotype. We recruited 63 clinically diagnosed with OCA patients in Gansu Provincial Maternal and Child Health Care Hospital. Mutation screening analysis was performed by direct sequencing and NGS-target sequencing to screen the variants on genes related to OCA. PolyPhen2 and PROVEN tools were used to predict the possible functional role of the novel variants. We assessed the pathogenicity of the novel mutations according to the clinical interpretation of genetic variants by ACMG/AMP 2015 guideline. By molecular testing, 56 of the OCA probands were diagnosed as OCA 1, three were OCA 2 and one was OCA 4. The most common variants of TYR were c.929insC(33.7%), c.896 G > A(12.5%), c.832 C > T(9.6%).We found five novel variants of TYR that have not previously been reported. We make an accurate diagnosis and classification for the OCA probands. Our result enlarged the mutational spectrum of TYR and SLC45A2. These findings could be useful for genetic counseling and gene diagnosis of OCA in Northwest of China. [ABSTRACT FROM AUTHOR]

The Italian Asinara donkey and the White Austro-Hungarian Baroque donkey share an identical coat colour phenotype which is characterised by unpigmented skin, white hair, white hooves and blue eyes. Whereas for the Asinara donkey the white coat colour phenotype was assigned to a recessive inherited missense mutation in the Tyrosinase gene (TYR), the underlying genetic background in the White Austro-Hungarian Baroque donkey has not been studied yet. Historical documents derived by the presence of Austro-Hungarian prisoners in the Asinara Island during the First World War might suggest a possible common origin of the same coat colour phenotype in the two breeds. Genotyping of this mutation in the TYR gene and the loci in the KIT gene associated with Dominant White and White Spotting phenotype, revealed, that none of the mutated alleles segregated in the White Austro-Hungarian Baroque Donkey breed. Also sequencing analysis of the TYR gene did not result in the detection of further candidate variants. Therefore, the TYR gene can be excluded as a possible candidate gene for this specific coat colour in the White Austro-Hungarian Baroque donkey. This result excludes a common genetic origin of the white coat colour of the Asinara and White Austro-Hungarian Baroque donkeys that historical documents could have suggested. Historical information indicated that the white (albino) Asinara donkey breed and the White Austro-Hungarian Baroque donkey breed could be genetically related. The TYR mutation identified in Asinara donkeys and known polymorphic sites in the KIT gene associated with depigmented white coat colour in donkeys do not segregate in the White Austro-Hungarian Baroque Donkey. Due to different underlying genetic background of one identical phenotype in two populations, no common ancestors can be assumed between Asinara donkey and White Austro-Hungarian Baroque donkey throughout the last century. [ABSTRACT FROM AUTHOR]

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