Variable disease severity in Saudi Arabian and Sudanese families with c.3924 + 2 T &gt; C mutation of LAMA2

Claudia Di Blasi,Kevin P Campbell,Christopher A Walsh,Zein A Karrar,Mustafa Am Salih,M Chiara Manzini,Steven A Moore,Renato Mantegazza,Marina Mora,Lucia Morandi,Maowia M Mukhtar,Mohammed Z Seidahmed,Emanuela Bellafiore

doi:10.1186/1756-0500-4-534

Abstract

BackgroundCongenital muscular dystrophy type 1A is caused by mutations in the LAMA2 gene that encodes the laminin α2 chain, a component of the skeletal muscle extracellular matrix protein laminin-211. The clinical spectrum of the disease is more heterogeneous than previously thought, particularly in terms of motor achievement and disease progression. We investigated clinical findings and performed molecular genetic analysis in 3 families from Saudi Arabia and 1 from Sudan in whom congenital muscular dystrophy 1A was suspected based on homozygosity mapping and laminin α2 chain deficiency.MethodsWe investigated 9 affected individuals from 1 Sudanese and 3 Saudi families in whom MDC1A was suggested by clinical, neuroimaging and/or pathological findings and by homozygosity mapping at the LAMA2 locus. Morphological and immunohistochemical analysis were performed in 3 patients from the 3 Saudi families. SSCP analysis, DNA sequencing and microsatellite analysis were carried out in the 4 index cases.ResultsA previously described mutation in the LAMA2 gene, a homozygous T > C substitution at position +2 of the consensus donor splice site of exon 26, was found in the 4 index patients. Clinical evaluation of 9 patients from the 4 families revealed variable disease severity particularly as regards motor achievement and disease progression. Microsatellite analysis showed an identical mutation-associated haplotype in the 4 index cases indicating a founder effect of the mutation in all 4 families.ConclusionsOur data provide further evidence that the clinical spectrum of MDC1A due to a single mutation is heterogeneous, particularly in terms of motor achievement and disease progression, making it difficult to give a reliable prognosis even in patients with identical LAMA2-associated haplotype. The c.3924 + 2 T > C mutation to date has been found only in patients originating from the Middle East or Sudan; therefore laminin 2 chain deficiency in patients from those regions should initially prompt a search for this mutation.

Highlights

Congenital muscular dystrophy type 1A is caused by mutations in the LAMA2 gene that encodes the laminin a2 chain, a component of the skeletal muscle extracellular matrix protein laminin-211
Congenital muscular dystrophy type 1A (MDC1A) is an autosomal recessive neuromuscular disorder caused by mutations in the LAMA2 gene encoding the laminin a2 chain [1] a component of the skeletal muscle extracellular matrix protein laminin-211 [2]
In the present study we report on three consanguineous Saudi Arabian families and a Sudanese family with the previously described [12] homozygous mutation c.3924 + 2 T > C in the LAMA2 gene

Summary

Introduction

Congenital muscular dystrophy type 1A is caused by mutations in the LAMA2 gene that encodes the laminin a2 chain, a component of the skeletal muscle extracellular matrix protein laminin-211. Congenital muscular dystrophy type 1A (MDC1A) is an autosomal recessive neuromuscular disorder caused by mutations in the LAMA2 gene encoding the laminin a2 chain [1] a component of the skeletal muscle extracellular matrix protein laminin-211 [2]. In the present study we report on three consanguineous Saudi Arabian families and a Sudanese family with the previously described [12] homozygous mutation c.3924 + 2 T > C in the LAMA2 gene This mutation leads to aberrant splicing of exon 26 and results in an inframe deletion of 63 amino acid residues from domain IVa of the laminin a2 chain. We performed haplotype analysis to investigate a hypothesized founder effect of this mutation, and examined the relationship between the mutation and clinical phenotype in the 4 families

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Discussion

Conclusion