Clinical, skeletal muscle pathological and genetic characteristics of fatal infantile hypertonic myofibrillar myopathy / 中华实用儿科临床杂志

Objective:To investigate the clinical, skeletal muscle pathological, and genetic characteristics of fatal infantile hypertonic myofibrillar myopathy (FIHMM).Methods:The clinical manifestations, laboratory assessments data and gene sequencing results of 10 patients diagnosed with FIHMM in Shenzhen Children′s Hospital from February 2017 to April 2021 were retrospectively analyzed.Magnetic resonance imaging (MRI) of both musculoskeletal system and the brain, and electromyogram (EMG) were performed in 3 cases, while muscle biopsy was performed in 2 cases.Results:Among these 10 cases, 1 case was from Northeast China and 1 case from East China, while the rest 8 cases were from South China.Eight of the 10 patients were male, and the other 2 cases were female.They were all born normal and not related to each other.The age of onset varied from 2 to 12 months.The main clinical manifestations for all the patients were progressive rigidity of the rectus abdominis (8 cases), neck muscles (7 cases), rectus abdominis (2 cases) and intercostal muscles (1 case), resulting in respiratory failure.Mildly to moderately elevated serum creatine kinase level was detected (436-5 804 IU/L) (reference range: 24-229 IU/L). Complex repetitive discharges can be seen in the EMG, without any myotonic potential.Muscle fiber degeneration, necrosis, and vacuolar degeneration were noted in the histopathological examination of the vastus lateralis and rectus abdominis.An abnormal red granular deposit was observed in a portion of the field of the modified Gomory Trichrome staining.Immunohistochemistry showed substantial deposition of desmin.Under the electron microscopy, the sarcomere structure of the muscle fibers was seriously disordered, with the destruction of Z-bands and the presence of granular deposits.The whole-exome sequencing identified the same homozygous variation c. 3G>A, p.Met1? of CRYAB gene in all the patients, but heterozygous variation in their parents. Conclusions:Axial muscles involvement, such as rectus abdominis rigidity, is the main clinical characteristic of FIHMM.c.3G>A, p.Met1? mutation in the CRYAB gene is a hotspot mutation in Chinese children.

A new heterozygous mutation in the stop codon of CRYAB (p.X176Y) is liable for congenital posterior pole cataract in a Chinese family.

Background: The present study aims to identify the underlying genetic defects in a Chinese family with autosomal dominant congenital cataracts (ADCC).Methods: Detailed family histories and clinical data were recorded. Targeted exome sequencing of 54 known cataract-associated genes combined with high-throughput next-generation sequencing was conducted followed by Sanger sequencing and bioinformatic analysis to identify the causative gene lesion for the family.Results: A four-generation Chinese family with posterior pole type cataract were enrolled. Enrichment of targeted genes revealed a new heterozygous p.X176Y mutation in the stop codon of αB-crystallin (CRYAB) gene, which resulted in the loss of the stop codon and prolongation of the mutant protein by 19 amino acid residues (p.X176Yfs19*). Sanger sequencing showed complete co-segregation with the disease. The elongated mutant protein was predicted to be pathogenic by forming new α-helix and random-coil in the secondary structure as well as producing an extended strand in the tertiary structure, potentially leading to increased hydrophobicity and reduced protein stability.Conclusions: Our report added a new mutation in the spectrum of congenital cataracts. The data suggested that X176 residue in the COOH-terminal is of crucial importance for the αB-crystallin protein function which was valuable for further study of the pathogenesis of congenital cataracts.Abbreviations:CRYAB: αB-crystallin; DNA: deoxyribonucleic acid; PCR: polymerase chain reaction; TES: targeted exome sequencing; ACD: αB-crystallin domain.

Genetic polymorphism of CRYAB gene rs3212227 and rs6894567 in Chinese guangxi populations / 重庆医学

Objective To study the frequencies of allele and genotype distribution of alpha-B-crystallin (CRYAB ) gene rs3212227 and rs6894567 single nucleotide polymorphism (SNP) in Chinese guangxi populations ,and to Compare the distribution differences among different ethnic .Methods The CRYAB gene rs3212227 and rs6894567 polymorphisms were detected by the pol-ymerase chain reaction-single base extension (PCR-SBE) technique and DNA sequencing methods in 199 Chinese guangxi popula-tions ,frequencies of allele and genotype of CRYAB gene SNP loci ,rs3212227、rs6894567 were analyzed in guangxi populations com-pared with other the four populations (HapMap-CEU ,HapMap-YRI ,HapMap-JPT and HapMap-HCB) from Human Genome Pro-ject group (Hapmap) data .Results There were CRYAB gene polymorphisms in Guangxi populations .The frequencies of allele and genotype distribution of CRYAB gene rs3212227、rs6894567 polymorphisms had significant difference compared with HapMap-CEU and HapMap-YRI populations (P0 .05) .Conclusion The frequencies of allele and genotype distribution of CRYAB gene rs3212227、rs6894567 polymorphisms are significantly difference compared with others ethnic populations ,and this variation might account for a variety of clinical mani-festation and morbidity of of some CRYAB related diseases .