Compound heterozygous DYSF variants causing limb-girdle muscular dystrophy type 2B in a Chinese family.

BACKGROUND: The dysferlin gene or the DYSF gene encodes the Ca2+ -dependent phospholipid-binding protein dysferlin, which belongs to the ferlin family and is associated with muscle membrane regeneration and repair. Variants in the DYSF gene are responsible for limb-girdle muscular dystrophy type 2B (LGMD2B), also called limb-girdle muscular dystrophy recessive 2 (LGMDR2), a rare subtype of muscular dystrophy involving progressive muscle weakness and atrophy. The present study aimed to identify the variants responsible for the clinical symptoms of a Chinese patient with limb girdle muscular dystrophies (LGMDs) and to explore the genotype-phenotype associations of LGMD2B. METHODS: A series of clinical examinations, including blood tests, magnetic resonance imaging scans for the lower legs, electromyography and muscle biopsy, was performed on the proband diagnosed with muscular dystrophies. Whole exome sequencing was conducted to detect the causative variants, followed by Sanger sequencing to validate these variants. RESULTS: We identified two compound heterozygous variants in the DYSF gene, c.1058 T>C, p.(Leu353Pro) in exon 12 and c.1461C>A/p.Cys487* in exon 16 in this proband, which were inherited from the father and mother, respectively. In silico analysis for these variants revealed deleterious results by PolyPhen-2 (Polymorphism Phenotyping v2; http://genetics.bwh.harvard.edu/pph2), SIFT (Sorting Intolerant From Tolerant; https://sift.bii.a-star.edu.sg), PROVEAN (Protein Variation Effect Analyzer; http://provean.jcvi.org/seq_submit.php) and MutationTaster (http://www.mutationtaster.org). In addition, the two compound heterozygous variants in the proband were absent in 100 control individuals who had an identical ethnic origin and were from the same region, suggesting that these variants may be the pathogenic variants responsible for the LGMD2B phenotypes for this proband. CONCLUSIONS: The present study broadens our understanding of the mutational spectrum of the DYSF gene, which provides a deep insight into the pathogenesis of LGMDs and accelerates the development of a prenatal diagnosis.

Mutations in ASH1L confer susceptibility to Tourette syndrome.

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by repetitive motor movements and vocal tics. The clinical manifestations of TS are complex and often overlap with other neuropsychiatric disorders. TS is highly heritable; however, the underlying genetic basis and molecular and neuronal mechanisms of TS remain largely unknown. We performed whole-exome sequencing of a hundred trios (probands and their parents) with detailed records of their clinical presentations and identified a risk gene, ASH1L, that was both de novo mutated and associated with TS based on a transmission disequilibrium test. As a replication, we performed follow-up targeted sequencing of ASH1L in additional 524 unrelated TS samples and replicated the association (P value = 0.001). The point mutations in ASH1L cause defects in its enzymatic activity. Therefore, we established a transgenic mouse line and performed an array of anatomical, behavioral, and functional assays to investigate ASH1L function. The Ash1l+/- mice manifested tic-like behaviors and compulsive behaviors that could be rescued by the tic-relieving drug haloperidol. We also found that Ash1l disruption leads to hyper-activation and elevated dopamine-releasing events in the dorsal striatum, all of which could explain the neural mechanisms for the behavioral abnormalities in mice. Taken together, our results provide compelling evidence that ASH1L is a TS risk gene.

Evaluation of Glutathione Peroxidase 4 role in Preeclampsia.

Preeclampsia (PE) is a pregnancy-specific syndrome that may be lifethreatening to pregnancies and fetus. Glutathione Peroxidase 4 (GPx4) is a powerful antioxidant enzyme that can provide protection from oxidative stress damage which plays a pivotal role in the pathology of PE. Therefore, this study aims to investigate the association between Gpx4 polymorphisms and the susceptibility to PE in Chinese Han women. TaqMan allelic discrimination real-time PCR was used to perform the genotyping of rs713041 and rs4807542 in 1008 PE patients and 1386 normotensive pregnancies. Obviously statistical difference of genotypic and allelic frequencies were found of rs713041 in GPx4 between PE patients and controls and the C allele has the higher risk for pathogenesis of PE (χ(2) = 12.292, P = 0.002 by genotype; χ(2) = 11.035, P = 0.001, OR = 1.216, 95% CI 1.084-1.365 by allele). Additionally, when subdividing these samples into CC + CT and TT groups, we found a significant difference between the two groups (χ(2) = 11.241, P = 0.001, OR = 1.417, 95% CI 1.155-1.738). Furthermore, the genotype of rs713041 was found to be associated with the mild, severe and early-onset PE. Our results suggest that rs713041 in GPx4 may play a key role in the pathogenesis of PE.