Limb girdle muscular dystrophy in a sibling pair with a homozygous Ser606Leu mutation in the alternatively spliced IS2 region of calpain 3
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Dieter E. Jenne
Abstract
Previous family studies revealed a large number of calpain 3 (CAPN3) mutations that cause recessive forms of limb girdle muscular dystrophy (LGMD2A) with selective atrophy of the proximal limb muscles. Correlations between the nature and site of a particular mutation and its corresponding phenotype, however, can only be established from homozygous mutations, which are particularly rare in the alternatively spliced NS, IS1 and IS2 regions of CAPN3. Here we identified a sibling pair with LGMD2A-type muscular dystrophy caused by a homozygous Ser606Leu (S606L) substitution in the IS2 linker domain. Normal protein levels, unaltered myofibrillar targeting and conserved calcium-induced autocatalytic activity of the mutated protein could be demonstrated in muscle biopsies from one patient. Despite this inconspicuous modification of the IS2 linker between domains III and IV, both patients developed signs and symptoms of the disease within their second decade of life. The unexpected severity of the clinical manifestation points to the high relevance of the calpain 3-specific IS2 segment between domains III and IV. We conclude that the structural motif around the Ser606 residue represents an important functional site that may regulate the transient activation and limited proteolysis of calpain 3.
References
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Artikel in diesem Heft
- The structure of the juvenile hormone binding protein gene from Galleria mellonella
- Interaction of thiamin diphosphate with phosphorylated and dephosphorylated mammalian pyruvate dehydrogenase complex
- Purification and characterization of a chitinase-like antifungal protein from black turtle bean with stimulatory effect on nitric oxide production by macrophages
- Nitric oxide covalently labels a 6-hydroxydopa-derived free radical intermediate in the catalytic cycle of copper/quinone-containing amine oxidase from lentil seedlings
- Plasmodium falciparum glutaredoxin-like proteins
- Characterization of the glyoxalases of the malarial parasite Plasmodium falciparum and comparison with their human counterparts
- Transcriptional down-regulation of neurotrophin-3 in chronic obstructive pulmonary disease
- Limb girdle muscular dystrophy in a sibling pair with a homozygous Ser606Leu mutation in the alternatively spliced IS2 region of calpain 3
- GRIP1 mediates the interaction between the amino- and carboxyl-termini of the androgen receptor
- Dual concentration-dependent activity of thyroglobulin type-1 domain of testican: specific inhibitor and substrate of cathepsin L
- Proteolysis of insulin-like growth factor binding proteins (IGFBPs) by calpain
