Brain, Vol. 123, No. 1, 31-41,
January 2000
© 2000 Oxford University Press
Mutations in the laminin 
2-chain gene in two children with early-onset muscular dystrophy
1 Neuromuscular Unit, Department of Paediatrics and Neonatal Medicine, 2 MRC Muscle Cell Biology Group, Hammersmith Hospital, London, Departments of 3 Paediatrics and 4 Neuropathology, Frenchay Hospital, Bristol, UK
Correspondence to:
Francesco Muntoni, MD, Professor and Consultant in Paediatric and Neonatal Medicine, Department of Paediatrics and Neonatal Medicine, Imperial College School Of Medicine, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK E-mail: fmuntoni{at}rpms.ac.uk
We investigated two children who presented with delayed motor milestones. The 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 independently mobile but has difficulty rising from the floor or going upstairs. The second was also a girl who presented at 6 weeks of age with hypotonia. Her motor milestones were delayed and she walked at the age of 2 years and 8 months and is currently independently mobile at the age of 3 years. Serum creatine kinase was elevated and a muscle biopsy showed dystrophic changes in both children. Immunohistochemistry of the laminin 
2 chain of merosin was 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 fragment showed a very marked reduction. Mutational analysis of the laminin 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 TC transition at position +6 of the conserved donor splicing consensus sequence of introns 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 alleles the same two splicing consensus sequence mutations found in cis in the first patient. Our data provide further evidence that mutations in the laminin 2 chain gene are responsible not only for the severe form of congenital muscular dystrophy with onset at birth, but also for milder phenotypes, with later onset, in which the synthesis of a partially functional protein, or of a normal protein but in reduced quantity, is possible. The finding that these two unrelated patients had the same unusual mutation in common might suggest that this is a relatively commonly allele responsible for partial merosin deficiency in the UK.
lamina 2 chain; merosin; partial deficiency; muscular dystrophy
CK = creatine kinase; DAGs = dystrophin-associated glycoproteins; LAMA2 = laminin 2 chain gene; PCR = polymerase chain reaction; SSCP = single strand conformation polymorphism
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