title: Limb girdle muscular dystrophy in a sibling pair with a homozygous Ser606Leu mutation in the alternatively spliced IS2 region of calpain 3.
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.
authors.affiliation: Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, D-82152 Martinsried, Germany. djenne@neuro.mpg.de
authors.forename: Dieter E
authors.initials: DE
authors.lastname: Jenne
authors.forename: Rudi A
authors.initials: RA
authors.lastname: Kley
authors.forename: Matthias
authors.initials: M
authors.lastname: Vorgerd
authors.forename: J Michael
authors.initials: JM
authors.lastname: Schröder
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.forename: Heike
authors.initials: H
authors.lastname: Reimann
authors.forename: Beate
authors.initials: B
authors.lastname: Albrecht
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Clemens R
authors.initials: CR
authors.lastname: Müller
authors.forename: Gerhard
authors.initials: G
authors.lastname: Meng
authors.forename: Christian C
authors.initials: CC
authors.lastname: Witt
authors.forename: Siegfried
authors.initials: S
authors.lastname: Labeit
mesh_terms: D017668:Age of Onset; D017398:Alternative Splicing; D020816:Amino Acid Motifs / Q000235:genetics; D019943:Amino Acid Substitution; D002154:Calpain / Q000235:genetics*; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis / Q000379:methods; D005091:Exons; D014644:Genetic Variation; D006720:Homozygote; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008958:Models, Molecular; D009124:Muscle Proteins / Q000235:genetics*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D010375:Pedigree; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D035781:Siblings
chemical_list: D007527:Isoenzymes; D009124:Muscle Proteins; C105884:CAPN3 protein, human; D002154:Calpain