Mild Congenital Muscular Dystrophy Research Articles

LamininL4 domain structure resembles adhesion modules in ephrin receptor and other transmembrane glycoproteins.

The ~800kDa laminin heterotrimer forms a distinctive cross-shaped structure that further self-assembles into networks within the extracellular matrix. The domains at the laminin chain termini, which engage in network formation and cell-surface interaction, are well understood both structurally and functionally. By contrast, the structures and roles of additional domains embedded within the limbs of the laminin cross have remained obscure. Here, we report the X-ray crystal structure, determined to 1.2Å resolution, of the human lamininα2 subunitL4b domain, site of an inframe deletion mutation associated with mild congenital muscular dystrophy. The α2L4b domain is an irregular β-sandwich with many short and broken strands linked by extended loops. The most similar known structures are the carbohydrate-binding domains of bacterial cellulases, the ephrin-binding domain of ephrin receptors, and MAM adhesion domains in various other eukaryotic cell-surface proteins. This similarity to mammalian adhesion modules, which was not predicted on the basis of amino acid sequence alone due to lack of detectable homology, suggests that laminin internal domains evolved from a progenitor adhesion molecule and may retain a role in cell adhesion in the context of the laminin trimer. The atomic coordinates and structure factors have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ, USA (http://www.rcsb.org/) under codes 4YEP and 4YEQ.

Mutation in the Fukutin-Gene (FKTN) as cause of a mild congenital muscular dystrophy

Aims: Defective glycosylation of alpha-dystroglycan as a cause of congenital or limb-girdle muscular dystrophies trigger a broad clinical spectrum varying from mild adult onset limb-girdle muscular dystrophies without brain malformation and cognitive deficits (LGMD2M) to severe congenital muscular dystrophies including brain malformation and central nervous dysfunction. Seven genes, in which mutations can cause defective glycosylation are currently known; FKRP, POMT1, POMT2, POMGnT1, FKTN, LARGE and DAG1. Outside of Japan only isolated cases of fukutin-related muscular dystrophies (LGMD2M) with childhood onset have been described. A steroid therapy seems to have a positive effect. We report on an 8 year old boy suffering from a mild congenital muscular dystrophy type C4 (MDDGC4) with mutation in the Fukutin-Gene. To our knowledge this has not been described before Methods: Our patient exhibited delayed motor development and muscular hypotonia, both commencing in infancy. Free walking at the age of 23 months. At the age of 18 months a elevated CK was revealed (2985U/l), as well as elevated AST (151U/l), ALT (223U/l) and LDH (1270U/l). With a muscle biopsy showing a dystrophic histologic pattern and the immunehistochemistry illustrating an absent sarcolemnal expression of alpha dystroglycan the genetic analysis of the FKRP gene was initiated, showing a normal genotype. A subsequent analysis of the Fukutin gene identified a stop mutation. A steroid treatmend was recommenden to the parents recently, who rejected this option for now. Results: A subsequent analysis of the Fukutin gene identified a heterozygous in-frame duplication within Exon 5 as well as a heterozygous stop mutation in Exon 6 of the fukutin gene Conclusion: In patients showing motor development delay, as well as significantly elevated CK and a dystrophic histologic pattern in the muscle biopsy while cognitive development and cerebral imaging are normal a fukutin-related myopathy should be considered after exlusion of a mutation of the FKRP gene; particularly, because the diagnosis has therapeutic consequence in terms of steroid treatment.

A novel POMT2 mutation causes mild congenital muscular dystrophy with normal brain MRI

We report a patient harboring a novel homozygous mutation of c.604T > G (p.F202V) in POMT2. He showed delayed psychomotor development but acquired the ability to walk at the age of 3 years and 10 months. His brain MRI was normal. No ocular abnormalities were seen. Biopsied skeletal muscle revealed markedly decreased but still detectable glycosylated forms of alpha-dystroglycan (α-DG). Our results indicate that mutations in POMT2 can cause a wide spectrum of clinical phenotypes as observed in other genes associated with α-dystroglycanopathy. Presence of small amounts of partly glycosylated α-DG may have a role in reducing the clinical symptoms of α-dystroglycanopathy.

Expression of laminin chains in skin in merosin-deficient congenital muscular dystrophy.

Laminin-2 (merosin) is a heterotrimer composed of alpha 2, beta 1 and gamma 1 chains. Approximately half of the cases with the classical form of congenital muscular dystrophy (CMD) have a deficiency of the laminin alpha 2 chain, encoded by the LAMA2 gene on chromosome 6q22. This disorder is often termed merosin-deficient CMD. Skeletal and cardiac muscle, and the peripheral and central nervous systems, all express laminin alpha 2 and can be affected in merosin-deficient CMD. Normal skin also expresses all three chains of laminin-2 at the epidermal/dermal junction, around hair follicles and in the sensory nerves. Skin biopsies can therefore be used to assess merosin status in patients. We show here an absence of laminin alpha 2 in skin from four cases of CMD with a severe phenotype and abnormal magnetic resonance image (MRI) of the brain, in contrast to normal expression in one case of mild CMD with normal MRI, and in five controls. An additional case of CMD had a partial deficiency of laminin alpha 2 in the skin and severe motor disability, but a normal MRI. Sensory nerves in this case showed normal expression of laminin alpha 2, in contrast to its absence in the severe cases. The expression of laminin beta 1 was also reduced in skin from cases of merosin-deficient CMD. In contrast to human fetal muscle, the laminin alpha 2 protein was not detected in fetal skin up to 23 weeks of gestation. The laminin beta 1 and gamma 1 chains, and the mRNA for laminin alpha 2, however, were present. Studies of mRNA of cultured skin cells suggest that fibroblasts are the major source of laminin alpha 2, not keratinocytes. Our data show that skin is useful for the assessment of merosin status in patients with CMD and that skin fibroblasts may be a useful source of tissue-specific RNA. In addition, we show that there is a tissue-specific difference in the developmental expression of the laminin alpha 2 protein.

Mild Congenital Muscular Dystrophy in Two Patients with an Internally Deleted Laminin 2-Chain

Congenital muscular dystrophy (CMD) is a group of clinically and genetically heterogeneous disorders inherited in an autosomal recessive mode. The alpha2-chain of laminin-2 (previously called merosin) has been shown by immunohistochemical and genetic analyses to be implicated in the pathogenesis of the 'classic' form of CMD. In the 'merosin-deficient' subgroup, which represents about half of the cases, more definite evidence of the involvement of the laminin alpha2-chain has recently been reported with the identification of mutations in the gene encoding the alpha2-chain of laminin 2 (LAMA2) in CMD patients. Here we report on two siblings from a consanguineous family expressing an internally deleted laminin alpha2-chain as a result of a splice site mutation in the LAMA2 gene which causes the splicing of exon 25. The predicted protein lacks 63 amino acids in domain IVa which forms a globular structure on the short arm of the alpha2-chain. Interestingly, these patients appear mildly affected compared to others who completely lack this protein. This situation presents a striking analogy with Becker muscular dystrophy, where in-frame deletions in the dystrophin gene result in the expression of a semi-functional protein and lead to a mild phenotype.