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A large fraction of DNA variants impairs pre-mRNA splicing in human hereditary disorders. Crigler-Najjar syndrome (CNS) is characterized by a severe unconjugated hyperbilirubinemia caused by variants in the UGT1A1 gene. We previously reported one CNS-type II patient with two splice-site variants in trans (c.864+5G>T and c.996+2_996+5del). According to MaxEntScan, both disrupt their corresponding donor sites (c.864+5G>T: 6.99 → 2.28; c.996+2_996+5del: 5.96 → −11.02), so they were selected for subsequent functional tests. Given the unavailability of patient RNA, we constructed an UGT1A1 splicing-reporter minigene with exons 1–4 to characterize the underlying splicing anomaly. The variant c.996+2_996+5del generated two aberrant transcripts, Δ(E2) (exon 2 skipping/64%) and ▼(E2q135) (intron retention of 135-nt/36%), which lead to the loss of 18 conserved amino-acids and the gain of 45 new ones of a critical functional domain, respectively. The c.864+5G>T variant mainly produced the aberrant transcript Δ(E1q141) (141-nt deletion/70.4%) and the full-length isoform (29.6%). Δ(E1q141) would provoke the loss of 47 amino-acids of the N-terminal domain that encodes for substrate specificity. Thus, the three anomalous transcripts are likely to inactivate UGT1A1. Moreover, this patient is also homozygous for the promoter variant A(TA)7TAA that decreases UGT1A1 expression by 70%, so the full-length transcript produced by c.864+5G>T would be even more reduced (

A large fraction of DNA variants impairs pre-mRNA splicing in human hereditary disorders. Crigler-Najjar syndrome (CNS) is characterized by a severe unconjugated hyperbilirubinemia caused by variants in the UGT1A1 gene. We previously reported one CNS-type II patient with two splice-site variants in trans (c.864+5G>T and c.996+2_996+5del). According to MaxEntScan, both disrupt their corresponding donor sites (c.864+5G>T: 6.99 → 2.28; c.996+2_996+5del: 5.96 → −11.02), so they were selected for subsequent functional tests. Given the unavailability of patient RNA, we constructed an UGT1A1 splicing-reporter minigene with exons 1–4 to characterize the underlying splicing anomaly. The variant c.996+2_996+5del generated two aberrant transcripts, Δ(E2) (exon 2 skipping/64%) and ▼(E2q135) (intron retention of 135-nt/36%), which lead to the loss of 18 conserved amino-acids and the gain of 45 new ones of a critical functional domain, respectively. The c.864+5G>T variant mainly produced the aberrant transcript Δ(E1q141) (141-nt deletion/70.4%) and the full-length isoform (29.6%). Δ(E1q141) would provoke the loss of 47 amino-acids of the N-terminal domain that encodes for substrate specificity. Thus, the three anomalous transcripts are likely to inactivate UGT1A1. Moreover, this patient is also homozygous for the promoter variant A(TA)7TAA that decreases UGT1A1 expression by 70%, so the full-length transcript produced by c.864+5G>T would be even more reduced (<9%), thus supporting the diagnosis of CNS-type II. Therefore, minigenes represent valuable tools for the functional and clinical classifications of genetic variants. [ABSTRACT FROM AUTHOR]

The potential for genetic variation to cause adult unconjugated hyperbilirubinemia is increasingly being recognized. However, the cumulative effects of genetic variants have not been fully illuminated. The current study aimed to investigate the effects of uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) and/or solute carrier organic anion transporter family member 1B (SLCO1B) polymorphic variants and their combined effects on mild unconjugated hyperbilirubinemia in Chinese adults. Fourteen genetic variants in the UGT1A1 or SLCO1B gene were genotyped through sequencing in 148 adults with unconjugated hyperbilirubinemia and 158 healthy controls. Variants c.-3275T > G, (TA)6>(TA)7, c.211G > A or c.1091C > T within the UGT1A1 gene as well as c.521T > C within the SLCO1B1 gene appear to be genetic risk factors for inherited unconjugated hyperbilirubinemia. After adjusting for covariates, the results of multivariate logistic regressions revealed that odds ratios (ORs) [(with 95% confidence interval (CI)] of these five variants were 2.35 (95% CI: 1.37–4.01, p = 0.002), 2.38 (95% CI: 1.35–4.20, p = 0.003), 2.99 (95% CI: 1.71–5.21, p < 0.001), 7.60 (95% CI: 1.99–28.96, p = 0.003), and 2.54 (95% CI: 1.27–5.11, p = 0.009), respectively. The OR for unconjugated hyperbilirubinemia is positively correlated with the cumulative number of these five variants in adults. And the greater the number of genetic variations, the higher the total bilirubin level. Adults carrying diplotype 3/4 (homozygous c.-3275T > G and heterozygous (TA)6>(TA)7) had higher bilirubin levels than those with diplotypes 1/3 (heterozygous c.-3275T > G and (TA)6>(TA)7)) or 1/4 (heterozygous c.-3275T > G) (P < 0.05). Similarly, bilirubin levels in individuals with diplotype 2/4 (heterozygous c.-3275T > G and c.211G > A) were higher than adults carrying diplotypes 1/2 (heterozygous c.211G > A) or 1/4 (P < 0.001). For subjects with heterozygous or homozygous variant c.211G> A, as the number of c.521T > C alleles variation increased, the incidence of unconjugated hyperbilirubinemia increased, but it was not statistically significant. Our results indicate that variants of UGT1A1 and/or SLCO1B1 have combined effects on Chinese adult mild unconjugated hyperbilirubinemia.

Background: Single nucleotide polymorphism (SNP) variants of the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene have been studied as an important factor in neonatal hyperbilirubinemia (jaundice) severity. Specific ethnicities, including Asians, have certain SNPs that appear more frequently than others.Aim: To identify the most common SNPs in Indonesian neonates and their association with the severity of neonatal hyperbilirubinemia.Methods: Eighty-eight inborn and outborn jaundiced infants from three different hospitals (Bengkulu, Jakarta, Biak Papua) across Indonesia were enrolled in this cross-sectional study and their peak total serum bilirubin (TSB) levels assessed. SNP variant analyses of the TATAA box, promoter, and exon 1 regions of UGT1A1 gene from 78 of the 88 infants were carried out using the SNaPshotR Multiplex Polymerase Chain Reaction (PCR) System followed by DNA sequencing.Results: We detected SNP variants UGT1A1*28, UGT1A1*60, UGT1A1*93, and UGT1A1*6 in our population. Mean total serum bilirubin (TSB) was 14.59 ± 5.57 mg/dL. Bivariate analyses using delivery location, gestational age, birth weight, mother's age, and ethnicity were shown to be associated with moderate-to-severe hyperbilirubinemia (p < 0.05). None of the four SNPs appeared to be associated with moderate-to-severe hyperbilirubinemia. In multivariate analysis, however, only the “other ethnic group” (e.g., Chinese, Bengkulu, Papua, Bima) category showed an association with moderate-to-severe hyperbilirubinemia, with an odds ratio of 6.49 (95% CI 1.01–41.67; p < 0.05).Conclusions: We found that the UGT1A1*60 is the most common SNP detected in neonates with hyperbilirubinemia in the Indonesian population. Interestingly, in Indonesia, UGT1A1 polymorphisms do not appear to be associated with differences in the severity of hyperbilirubinemia.

The potential for genetic variation to cause adult unconjugated hyperbilirubinemia is increasingly being recognized. However, the cumulative effects of genetic variants have not been fully illuminated. The current study aimed to investigate the effects of uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) and/or solute carrier organic anion transporter family member 1B (SLCO1B) polymorphic variants and their combined effects on mild unconjugated hyperbilirubinemia in Chinese adults. Fourteen genetic variants in the UGT1A1 or SLCO1B gene were genotyped through sequencing in 148 adults with unconjugated hyperbilirubinemia and 158 healthy controls. Variants c.-3275T > G, (TA)6>(TA)7, c.211G > A or c.1091C > T within the UGT1A1 gene as well as c.521T > C within the SLCO1B1 gene appear to be genetic risk factors for inherited unconjugated hyperbilirubinemia. After adjusting for covariates, the results of multivariate logistic regressions revealed that odds ratios (ORs) [(with 95% confidence interval (CI)] of these five variants were 2.35 (95% CI: 1.37–4.01, p = 0.002), 2.38 (95% CI: 1.35–4.20, p = 0.003), 2.99 (95% CI: 1.71–5.21, p < 0.001), 7.60 (95% CI: 1.99–28.96, p = 0.003), and 2.54 (95% CI: 1.27–5.11, p = 0.009), respectively. The OR for unconjugated hyperbilirubinemia is positively correlated with the cumulative number of these five variants in adults. And the greater the number of genetic variations, the higher the total bilirubin level. Adults carrying diplotype 3/4 (homozygous c.-3275T > G and heterozygous (TA)6>(TA)7) had higher bilirubin levels than those with diplotypes 1/3 (heterozygous c.-3275T > G and (TA)6>(TA)7)) or 1/4 (heterozygous c.-3275T > G) (P < 0.05). Similarly, bilirubin levels in individuals with diplotype 2/4 (heterozygous c.-3275T > G and c.211G > A) were higher than adults carrying diplotypes 1/2 (heterozygous c.211G > A) or 1/4 (P < 0.001). For subjects with heterozygous or homozygous variant c.211G> A, as the number of c.521T > C alleles variation increased, the incidence of unconjugated hyperbilirubinemia increased, but it was not statistically significant. Our results indicate that variants of UGT1A1 and/or SLCO1B1 have combined effects on Chinese adult mild unconjugated hyperbilirubinemia. [ABSTRACT FROM AUTHOR]

Some authors suggest a relation between Unconjugated Bilirubin (UCB) plasma high levels and schizophrenia, as schizophrenia patients have been showing higher UCB levels when compared with other psychiatric patients and general population. These higher UCB levels have been already correlated with acute psychotic states, positive symptoms, and poor outcome in patients with schizophrenia. Schizophrenia and schizoaffective disorders share common symptoms but there aren't yet accepted biomarkers for their distinction. In our study protocol we propose an observational longitudinal study on a sample composed of two subgroups: patients with schizophrenia and patients with schizoaffective disorder. We will compare the UCB levels between groups, and search for a possible correlation with patient's psychopathology. For that purpose we will use nosological, psychopathological, neuropsychological, and psychosocial instruments. Thus we will be testing two different hypotheses: (1) Is UCB serum level a diagnosis indicator, with categorical distinction potential, between groups of patients with different psychotic disorders? (2) Is UCB serum level a severity indicator, with dimensional distinction potential, among groups of patients with the same psychotic disorder? We believe that UCB mean levels may contribute to some clarification of this controversy, as a potential biological indicator, facilitating the distinction between these two diagnostic categories and\or discriminating the dimensional severity among each of these psychotic conditions. Thus we may be opening a new opportunities for innovative and exciting biological psychiatry research regarding organic aspects in the schizophrenia spectrum.

Some authors suggest a relation between Unconjugated Bilirubin (UCB) plasma high levels and schizophrenia, as schizophrenia patients have been showing higher UCB levels when compared with other psychiatric patients and general population. These higher UCB levels have been already correlated with acute psychotic states, positive symptoms, and poor outcome in patients with schizophrenia. Schizophrenia and schizoaffective disorders share common symptoms but there aren't yet accepted biomarkers for their distinction. In our study protocol we propose an observational longitudinal study on a sample composed of two subgroups: patients with schizophrenia and patients with schizoaffective disorder We will compare the UCB levels between groups, and search for a possible correlation with patient's psychopathology. For that purpose we will use nosological, psychopathological, neuropsychological, and psychosocial instruments. Thus we will be testing two different hypotheses: (1) Is UCB serum level a diagnosis indicator, with categorical distinction potential, between groups of patients with different psychotic disorders? (2) Is UCB serum level a severity indicator, with dimensional distinction potential, among groups of patients with the same psychotic disorder? We believe that UCB mean levels may contribute to some clarification of this controversy, as a potential biological indicator, facilitating the distinction between these two diagnostic categories and\or discriminating the dimensional severity among each of these psychotic conditions. Thus we may be opening a new opportunities for innovative and exciting biological psychiatry research regarding organic aspects in the schizophrenia spectrum. [ABSTRACT FROM AUTHOR]

Unconjugated hyperbilirubinemia is a common condition in the first week of postnatal life. Although generally harmless, some neonates may develop very high levels of unconjugated bilirubin (UCB), which may surpass the protective mechanisms of the brain at preventing UCB accumulation. In this case, both short-term and long-term neurodevelopmental disabilities, such as acute and chronic UCB encephalopathy, known as kernicterus, or more subtle alterations designed as bilirubin-induced neurological dysfunction (BIND) may be produced. There is a tremendous variability in babies’ vulnerability towards UCB for reasons not yet explained, but preterm birth, sepsis, hypoxia and haemolytic disease are comprised as risk factors. Therefore, UCB levels and neurological abnormalities are not strictly correlated. Even nowadays, the mechanisms of UCB neurotoxicity are still unclear, as are specific biomarkers, and little is known about lasting sequelae attributable to hyperbilirubinemia. On autopsy, UCB was shown to be within neurons, neuronal processes and microglia, and to produce loss of neurons, demyelination and gliosis. In isolated cell cultures, UCB was shown to impair neuronal arborization and to induce the release of proinflammatory cytokines from microglia and astrocytes. However, cell dependent-sensitivity to UCB toxicity and the role of each nerve cell type remain understood. This review provides a comprehensive insight into cell susceptibilities and molecular targets of UCB in neurons, astrocytes, and oligodendrocytes, and on phenotypic and functional responses of microglia to UCB. Interplay among glia elements and cross-talk with neurons, with a special emphasis in the UCB-induced immunostimulation, and the role of sepsis in BIND pathogenesis are highlighted. New and interesting data on the anti-inflammatory and antioxidant activities of different pharmacological agents are also presented, as novel and promising additional therapeutic approaches to BIND.