Laminin α2 muscular dystrophy

Authors:
  • HMH. Marks
    H. Marks
  • CGC. A. Garcia
    C. A. Garcia
  • TCT. Crawford
    T. Crawford
  • PMP. Mancias
    P. Mancias
  • ACA. M. Connolly
    A. M. Connolly
  • MFM. Fanin
    M. Fanin
  • FMF. Martinello
    F. Martinello
  • CTC. P. Trevisan
    C. P. Trevisan
  • MSM. Scavina
    M. Scavina
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Abstract
Objective: To determine the number of primary laminin α2 gene mutations and to conduct genotype/phenotype correlation in a cohort of lamininα2-deficient congenital muscular dystrophy patients. Background: Congenital muscular dystrophies (CMD) are a heterogenous group of muscle disorders characterized by early onset muscular dystrophy and a variable involvement of the CNS. Laminin α2 deficiency has been reported in about 40 to 50% of cases of the occidental, classic type of CMD.1,2 Laminin α2 is a muscle specific isoform of laminin localized to the basal lamina of muscle fibers, where it is thought to interact with myofiber membrane receptor, such as integrins, and possibly dystrophin-associated glycoproteins.3,4 Methods: Seventy-five CMD patients were tested for laminin α2 expression by immunofluorescence and immunoblot. The entire 10 kb laminin α2 coding sequence of 22 completely laminin α2-deficient patients was screened for causative mutations by reverse transcription (RT)-PCR/single strand conformational polymorphisms (SSCP) analysis and protein truncation test(PTT) analysis followed by automatic sequencing of patient cDNA. Clinical data from the laminin α2-deficient patients were collected. Results: Thirty laminin α2-negative patients were identified (40% of CMD patients tested) and 22 of them were screened for laminin α2 mutations. Clinical features of laminin α2-deficient patients were similar, with severe floppiness at birth, delay in achievement of motor milestones, and MRI findings of white matter changes with normal intelligence. Loss-of-function mutations were identified in 95% (21/22) of the patients studied. SSCP analysis detected laminin α2 gene mutations in about 50% of the mutant chromosomes; PTT successfully identified 75% of the mutations. A two base pair deletion mutation at position 2,096-2,097 bp was present in 23% of the patients analyzed. Conclusions: Our data suggest that the large majority of laminin α2-deficient patients show laminin α2 gene mutations.

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