title: myotilin Mutation found in second pedigree with LGMD1A.
abstract: Limb-girdle muscular dystrophy 1A (LGMD1A [MIM 159000]) is an autosomal dominant form of muscular dystrophy characterized by adult onset of proximal weakness progressing to distal muscle weakness. We have reported elsewhere a mutation in the myotilin gene in a large, North American family of German descent. Here, we report the mutation screening of an additional 86 families with a variety of neuromuscular pathologies. We have identified a new myotilin mutation in an Argentinian pedigree with LGMD1 that is predicted to result in the conversion of serine 55 to phenylalanine (S55F). This mutation has not been found in 392 control chromosomes and is located in the unique N-terminal domain of myotilin, only two residues from the T57I mutation reported elsewhere. Both T57I and S55F are located outside the alpha-actinin and gamma-filamin binding sites within myotilin. The identification of two independent pedigrees with the same disease, each bearing a different mutation in the same gene, has long been the gold standard for establishing a causal relationship between defects in a gene and the resultant disease. As a description of the second known pedigree with LGMD1A, this finding constitutes that gold standard of proof that mutations in the myotilin gene cause LGMD1A.
authors.affiliation: Duke University, Durham, NC 27710, USA. mhauser@chg.mc.duke.edu
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hauser
authors.forename: Cecilia B
authors.initials: CB
authors.lastname: Conde
authors.forename: Valeria
authors.initials: V
authors.lastname: Kowaljow
authors.forename: Guillermo
authors.initials: G
authors.lastname: Zeppa
authors.forename: Ana L
authors.initials: AL
authors.lastname: Taratuto
authors.forename: Udana M
authors.initials: UM
authors.lastname: Torian
authors.forename: Jeffery
authors.initials: J
authors.lastname: Vance
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Marcy C
authors.initials: MC
authors.lastname: Speer
authors.forename: Alberto L
authors.initials: AL
authors.lastname: Rosa
mesh_terms: D001118:Argentina; D064211:Connectin; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008840:Microfilament Proteins; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics*; D009136:Muscular Dystrophies / Q000145:classification* / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
chemical_list: D064211:Connectin; D003598:Cytoskeletal Proteins; C577290:MYOT protein, human; D008840:Microfilament Proteins; D009124:Muscle Proteins