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Hereditary spastic paraplegia (HSP) is a category of neurodegenerative illnesses with significant clinical and genetic heterogeneity. Homozygous truncated variants of the ERLIN2 gene lead to HSP18 (MIM #611225). However, it is still unclear whether there is an autosomal dominant pathogenic pattern. The specific molecular mechanism needs to be investigated. We generated patient-derived iPSC models to study the mechanism of ERLIN2 heterogeneous variants leading to HSP. We identified a heterozygous missense variant p.Val71Ala of ERLIN2 in an HSP family. Based on IP-mass spectrometry, we found that the ERLIN2 heterozygous missense variant protein recruited the ubiquitin E3 ligase RNF213 to degrade IP3R1. The degradation of IP3R1 leads to the reduction of intracellular free calcium, which triggered endoplasmic reticulum (ER) stress-mediated apoptosis. Calcium homeostasis imbalance inhibited the MAPK signaling pathway that contributed to decreased cell proliferation. In summary, these results suggest that the autosomal dominant inheritance of heterozygous missense variants in ERLIN2 is a novel pathogenic mode of HSP. Furthermore, the disruption of intracellular calcium homeostasis is the pathological mechanism.

Mutations of NKX2-5 largely contribute to congenital heart diseases (CHDs), especially atrial septal defect (ASD). We identified a novel heterozygous splicing mutation c.335-1G gt; A in NKX2-5 gene in an ASD family via whole exome sequencing (WES) and linkage analysis. Utilizing the human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs) as a disease model, we showed that haploinsufficiency of NKX2-5 contributed to aberrant orchestration of apoptosis and proliferation in ASD patient-derived hiPSC-CMs. RNA-seq profiling and dual-luciferase reporter assay revealed that NKX2-5 acts upstream of PYK2 via miR-19a and miR-19b (miR-19a/b) to regulate cardiomyocyte apoptosis. Meanwhile, miR-19a/b are also downstream mediators of NKX2-5 during cardiomyocyte proliferation. The novel splicing mutation c.335-1G gt; A in NKX2-5 and its potential pathogenic roles in ASD were demonstrated. Our work provides clues not only for deep understanding of NKX2-5 in cardia development, but also for better knowledge in the molecular mechanisms of CHDs.

BackgroundSpinocerebellar ataxia type 3 (SCA3) is a rare movement disorder characterized with ataxia. Previous studies on movement disorders show that the whole-brain functional network tends to be more regular, and these reconfigurations correlate with genetic and clinical variables.MethodsTo test whether the brain network in patients with SCA3 follows a similar reconfiguration course to other movement disorders, we recruited 41 patients with SCA3 (mean age = 40.51 ± 12.13 years; 23 male) and 41 age and sex-matched healthy individuals (age = 40.10 ± 11.56 years; 24 male). In both groups, the whole-brain network topology of resting-state functional magnetic resonance imaging (rs-fMRI) was conducted using graph theory, and the relationships among network topologies, cytosine-adenine-guanine (CAG) repeats, clinical symptoms, and functional connectivity were explored in SCA3 patients using partial correlation analysis, controlling for age and sex.ResultsThe brain networks tended to be more regular with a higher clustering coefficient, local efficiency, and modularity in patients with SCA3. Hubs in SCA3 patients were reorganized as the number of hubs increased in motor-related areas and decreased in cognitive areas. At the global level, small-worldness and normalized clustering coefficients were significantly positively correlated with clinical motor symptoms. At the nodal level, the clustering coefficient and local efficiency increased significantly in the visual (bilateral cuneus) and sensorimotor (right cerebellar lobules IV, V, VI) networks and decreased in the cognitive areas (right middle frontal gyrus). The clustering coefficient and local efficiency in the bilateral cuneus gyrus were negatively correlated with clinical motor symptoms. The functional connectivity between right caudate nucleus and bilateral calcarine gyrus were negatively correlated with disease duration, while connectivity between right posterior cingulum gyrus and left cerebellar lobule III, left inferior occipital gyrus and right cerebellar lobule IX was positively correlated.ConclusionOur results demonstrate that a more regular brain network occurred in SCA3 patients, with motor and visual-related regions, such as, cerebellar lobules and cuneus gyrus, both forayed neighbor nodes as “resource predators” to compensate for normal function, with motor and visual function having the higher priority comparing with other high-order functions. This study provides new information about the neurological mechanisms underlying SCA3 network topology impairments in the resting state, which give a potential guideline for future clinical treatments.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [ChiCTR1800019901].

Purpose: The single nucleotide polymorphism (SNP) rs2257440 in exon 1 of the gene DcR3 is known to be significantly associated with susceptibility to esophageal squamous cell carcinoma (ESCC). In the present study, bioinformatics analysis indicated that the SNP might influence the binding of a transcription factor, metal regulatory transcription factor 1 (MTF-1), to its target gene. We further investigated whether the polymorphism rs2257440 could regulate DcR3 expression as a functional SNP via MTF-1. Methods and Results: Luciferase reporter assay indicated that MTF-1 elevated the expression of luciferase in the presence of the T allele of rs2257440 while no change in the expression was associated with the C allele of the polymorphism. Chromatin immunoprecipitation further evaluated the binding between the locus harboring the T allele and MTF-1. In the case of the TC genotype, over-expression of MTF-1 elevated DcR3 expression, which in turn promoted the invasion capacity of KYSE450 cells. However, there was no significant change in the invasion capacity of EC109 cells, which had the CC genotype. In the cancer cells of the ESCC patients, the expression of DcR3 was higher in the case of the TC or TT genotypes in comparison to the gene expression associated with the CC genotype. Over-expression of MTF-1 also decreased apoptosis of EC109 and KYSE450 cells, but the decrement was more in KYSE450 cells than in EC109 cells. Conclusions: Our finding indicates that rs2257440 is a functional SNP. The T allele of rs2257440 can increase DcR3 expression as it promotes binding of the gene with the specific transcription factor MTF-1. Therefore, the T allele of this polymorphism can decrease apoptosis and promote the invasion capacity of the cells in ESCC.

LMNA gene encodes the ubiquitous protein lamin A/C, which is a component of the fibrous meshwork of intermediate filaments located at the inner surface of the nuclear envelope (Worman 2012). Lamin A/C are splicing variants encoded by the LMNA gene and share the first 566 amino acids. Mutations in LMNA gene are recently known to be responsible for more than 10 different clinical syndromes, most of which show overlapping features. Worman and Bonne (2007) classified the disorders into four major types: diseases of skeletal and cardiac muscle, lipodystrophy syndromes, peripheral neuropathy and premature ageing. Of the skeletal and cardiac muscles types, limb–girdle muscular dystrophy type 1B (LGMD1B), autosomal dominant Emery–Dreifuss muscular dystrophy 2 (EDMD2) and dilated cardiomyopathy 1A (CMD1A) are common (Capell and Collins 2006). Among the muscle type disorders related to LMNA gene mutations, LGMD1B is slowly progressive, with age-related atrioventricular cardiac conduction disturbance, dilated cardiomyopathy, muscle weakness and the absence of early contractures. However, EDMD2 is characterized by early contractures of elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and cardiomyopathywith a variable degree of conduction system disease (Capell and Collins 2006). In this report, we characterized a large Chinese family with atrioventricular block (AVB) as the most prominent feature, with concomitant moderate pelvic limb skeletal muscle defects. Due to the medical history, clinical manifestations and neurological/cardiological examinations, this family was diagnosed with autosomal LGMD1B. Then, a mutation