title: Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis.
abstract: Arthrogryposis multiplex congenita (AMC) is a group of disorders characterized by congenital joint contractures caused by reduced fetal movements. AMC has an incidence of 1 in 3000 newborns and is genetically heterogeneous. We describe an autosomal recessive form of myogenic AMC in a large consanguineous family. The disease is characterized by bilateral clubfoot, decreased fetal movements, delay in motor milestones, then progressive motor decline after the first decade. Genome-wide linkage analysis revealed a single locus on chromosome 6q25 with Z(max) = 3.55 at theta = 0.0 and homozygosity of the polymorphic markers at this locus in patients. Homozygous A to G nucleotide substitution of the conserved AG splice acceptor site at the junction of intron 136 and exon 137 of the SYNE-1 gene was found in patients. This mutation results in an aberrant retention of intron 136 of SYNE-1 RNA leading to premature stop codons and the lack of the C-terminal transmembrane domain KASH of nesprin-1, the SYNE-1 gene product. Mice lacking the KASH domain of nesprin-1 display a myopathic phenotype similar to that observed in patients. Altogether, these data strongly suggest that the splice site mutation of SYNE-1 gene found in the family is responsible for AMC. Recent reports have shown that mutations of the SYNE-1 gene might be responsible for autosomal recessive adult onset cerebellar ataxia. These data indicate that mutations of nesprin-1 which interacts with lamin A/C may lead to at least two distinct human disease phenotypes, myopathic or neurological, a feature similar to that found in laminopathies.
authors: Altura Department of Human Genetics, Hebrew University Hospital, Jerusalem, Israel.
authors: Ruben
authors: R
authors: Attali
authors: Nasim
authors: N
authors: Warwar
authors: Ariel
authors: A
authors: Israel
authors: Irina
authors: I
authors: Gurt
authors: Elizabeth
authors: E
authors: McNally
authors: Megan
authors: M
authors: Puckelwartz
authors: Benjamin
authors: B
authors: Glick
authors: Yoram
authors: Y
authors: Nevo
authors: Ziva
authors: Z
authors: Ben-Neriah
authors: Judith
authors: J
authors: Melki
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001176:Arthrogryposis / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002478:Cells, Cultured; D002896:Chromosomes, Human, Pair 6; D003598:Cytoskeletal Proteins; D004198:Disease Susceptibility; D005260:Female; D005808:Genes, Recessive; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D034881:Nuclear Lamina / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree
chemical_list: D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C415465:SYNE1 protein, human