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A novel dominant D109A CRYAB mutation in a family with myofibrillar myopathy affects ?B-crystallin structure.

ABSTRACT: Myofibrillar myopathy (MFM) is a group of inherited muscular disorders characterized by myofibrils dissolution and abnormal accumulation of degradation products. So far causative mutations have been identified in nine genes encoding Z-disk proteins, including ?B-crystallin (CRYAB), a small heat shock protein (also called HSPB5). Here, we report a case study of a 63-year-old Polish female with a progressive lower limb weakness and muscle biopsy suggesting a myofibrillar myopathy, and extra-muscular multisystemic involvement, including cataract and cardiomiopathy. Five members of the proband's family presented similar symptoms. Whole exome sequencing followed by bioinformatic analysis revealed a novel D109A mutation in CRYAB associated with the disease. Molecular modeling in accordance with muscle biopsy microscopic analyses predicted that D109A mutation influence both structure and function of CRYAB due to decreased stability of oligomers leading to aggregate formation. In consequence disrupted sarcomere cytoskeleton organization might lead to muscle pathology. We also suggest that mutated RQDE sequence of CRYAB could impair CRYAB chaperone-like activity and promote aggregation of lens crystallins.

SUBMITTER: Fichna JP

PROVIDER: S-EPMC5124346 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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A novel dominant D109A <i>CRYAB</i> mutation in a family with myofibrillar myopathy affects αB-crystallin structure.

Fichna Jakub P JP Potulska-Chromik Anna A Miszta Przemysław P Redowicz Maria Jolanta MJ Kaminska Anna M AM Zekanowski Cezary C Filipek Sławomir S

BBA clinical 20161111

Myofibrillar myopathy (MFM) is a group of inherited muscular disorders characterized by myofibrils dissolution and abnormal accumulation of degradation products. So far causative mutations have been identified in nine genes encoding Z-disk proteins, including αB-crystallin (CRYAB), a small heat shock protein (also called HSPB5). Here, we report a case study of a 63-year-old Polish female with a progressive lower limb weakness and muscle biopsy suggesting a myofibrillar myopathy, and extra-muscul ...[more]

PMID: 27904835

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Project description:BackgroundFatal infantile hypertonic myofibrillar myopathy (FIHMM) is an autosomal recessive hereditary disease characterized by amyotrophy, progressive flexion contracture and ankylosis of the trunk and limb muscles, apnea and respiratory failure, and increased creatine phosphate levels. It is caused by mutations in the CRYAB gene, and only around 18 cases including genetic mutations have been reported worldwide. All patients with FIHMM develop respiratory distress, progressive stiffness of the limbs, and have a poor prognosis. However, no effective treatment for CRYAB-associated respiratory failure has been reported. Here, we report a case of FIHMM with a novel heterozygous missense mutation.Case presentationA 2-year-old female developed scoliosis of the lumbar spine and restrictive ventilatory dysfunction in infancy. She was admitted to the hospital with labored breathing on the third day after the second injection of inactivated poliomyelitis vaccine. Acute respiratory failure, pneumothorax, and cardiac arrest arose in the patient during hospitalization, and progressive stiffness of the trunk and limb muscles appeared, accompanied by obvious abdominal distension and an increase in phosphocreatine kinase levels. Screenings for genetic metabolic diseases in the blood and urine were normal. Electromyography revealed mild myogenic damage. A muscle biopsy indicated the accumulation of desmin, α-crystallin, and myotilin in the musculus biceps brachii, and dense granules were observed in muscle fibers using electron microscopy. Mutation analysis of CRYAB revealed a novel heterozygous missense mutation in the proband, c.302A > C (p.His101Pro) and c.3G > A (p.Met1Ile), which inherited from her asymptomatic, heterozygous carrier parents, respectively. The proband was finally diagnosed as FIHMM. One month after the FIHMM diagnosis, the child died of respiratory failure.ConclusionWe report a case of FIHMM with a novel heterozygous missense mutation of CRYAB. This finding might improve our understanding of FIHMM and highlight a novel mutation in the Chinese population.

Project description:ImportanceNew genomic strategies can now be applied to identify a diagnosis in patients and families with previously undiagnosed rare genetic conditions. The large family evaluated in the present study was described in 1966 and now expands the phenotype of a known neuromuscular gene.ObjectiveTo determine the genetic cause of a slowly progressive, autosomal dominant, scapuloperoneal neuromuscular disorder by using linkage and exome sequencing.Design, setting, and participantsFourteen affected individuals in a 6-generation family with a progressive scapuloperoneal disorder were evaluated. Participants were examined at pediatric, neuromuscular, and research clinics from March 1, 2005, to May 31, 2014. Exome and linkage were performed in genetics laboratories of research institutions.Main outcomes and measuresExamination and evaluation by magnetic resonance imaging, ultrasonography, electrodiagnostic studies, and muscle biopsies (n = 3). Genetic analysis included linkage analysis (n = 17) with exome sequencing (n = 7).ResultsClinical findings included progressive muscle weakness in an initially scapuloperoneal and distal distribution, including wrist extensor weakness, finger and foot drop, scapular winging, mild facial weakness, Achilles tendon contractures, and diminished or absent deep tendon reflexes. Both age at onset and progression of the disease showed clinical variability within the family. Muscle biopsy specimens demonstrated type I fiber atrophy and trabeculated fibers without nemaline rods. Analysis of exome sequences within the linkage region (4.8 megabases) revealed missense mutation c.591C>A p.Glu197Asp in a highly conserved residue in exon 4 of ACTA1. The mutation cosegregated with disease in all tested individuals and was not present in unaffected individuals.Conclusions and relevanceThis family defines a new scapuloperoneal phenotype associated with an ACTA1 mutation. A highly conserved protein, ACTA1 is implicated in multiple muscle diseases, including nemaline myopathy, actin aggregate myopathy, fiber-type disproportion, and rod-core myopathy. To our knowledge, mutations in Glu197 have not been reported previously. This residue is highly conserved and located in an exposed position in the protein; the mutation affects the intermolecular and intramolecular electrostatic interactions as shown by structural modeling. The mutation in this residue does not appear to lead to rod formation or actin accumulation in vitro or in vivo, suggesting a different molecular mechanism from that of other ACTA1 diseases.

Dataset Information

A novel dominant D109A CRYAB mutation in a family with myofibrillar myopathy affects ?B-crystallin structure.

Publications

A novel dominant D109A <i>CRYAB</i> mutation in a family with myofibrillar myopathy affects αB-crystallin structure.

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