Mutations in the laminin alpha 2-chain gene in two children with early-onset muscular dystrophy

We investigated two children who presented with delayed motor milestones, T he first was a girl who was referred at 20 months because of developmental delay. She walked at 28 months and currently, aged 5 years, is independentl y mobile but has difficulty rising from the floor or going upstairs. The se cond was also a girl who presented at 6 weeks of age with hypotonia, Her mo tor milestones were delayed and she walked at the age of 2 years and 8 mont hs and is currently independently mobile at tbe age of 3 years. Serum creat ine kinase was elevated and a muscle biopsy showed dystrophic changes in bo th children. Immunohistochemistry of the laminin alpha 2 chain of merosin w as very similar in both cases: using a C-terminal antibody that recognizes an 80 kDa fragment, there was a mild reduction in expression on most fibres , while the staining with another antibody that recognizes a 300 kDa fragme nt showed a very marked reduction. Mutational analysis of the laminin alpha 2 chain gene in the first patient showed that one of the two alleles had a de novo single nucleotide deletion at position 5702, causing a frameshift, In the other allele, we identified two point mutations present in cis; one was a G-->C transition at position +5 while the second was a T-->C transit ion at position +6 of the conserved donor splicing consensus sequence of in trons 37 and 63, respectively, Transcription analysis of the corresponding cDNA region did not show any alternative splicing occurring as a result of these splice site mutations, Therefore, these mutations probably affect the splicing efficiency, Interestingly, the second child carried in both allel es the same two splicing consensus sequence mutations found in cis in the f irst patient. Our data provide further evidence that mutations in the lamin in alpha 2 chain gene are responsible not only for the severe form of conge nital muscular dystrophy with onset at birth, but also for milder phenotype s, with later onset, ire which the synthesis of a partially functional prot ein, or of a normal protein but in reduced quantity, is possible. The findi ng that these two unrelated patients had the same unusual mutation in commo n might suggest that this is a relatively commonly allele responsible for p artial merosin deficiency in the UK.