A recessively transmitted fatal hypertonic infantile muscular dystrophy has been described in Canadian aboriginals. The affected infants present with progressive limb and axial muscle stiffness and develop severe respiratory insufficiency, and most die in the first year of life. We sought to determine the genetic basis of this disease.
We performed histochemical, immunocytochemical, electron microscopy, and molecular genetic studies in a cohort of 12 patients affected by this disease.
Conventional histochemical and electron microscopy studies suggested myofibrillar myopathy (MFM). Therefore, we searched for ectopic expression of multiple proteins typical of MFM. Alpha B-crystallin (aBC) expression was absent from all fibers using a monoclonal antibody raised against the entire protein. However, a monoclonal antibody directed against the first 10 residues of aBC immunostained portions of abnormal fibers. Pursuing this clue, we searched for mutations in the gene for aBC (CRYAB) in available DNA samples of 8 patients. All harbored a homozygous deletion, c.60C, predicting a Ser to Ala change at codon 21 and a stop codon after 23 missense residues (p.Ser21AlafsX24). Clinically unaffected parents were heterozygous for this mutation.
The homozygous c.60delC in CRYAB pinpoints the genetic basis of the fatal infantile hypertonic muscular dystrophy of Canadian aboriginals. MFMs are typically transmitted by dominant inheritance, but in this disease the parental phenotype is rescued by limited expression of the highly truncated nonfunctional mutant gene product. The severe patient phenotype is due to homozygosity for the markedly hypomorphic allele. Ann Neurol, 2011.
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