Human Molecular Genetics Advance Access originally published online on June 19, 2009
Human Molecular Genetics 2009 18(18):3462-3469; doi:10.1093/hmg/ddp290
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Mutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposis
1 Monique and Jacques Roboh Research Laboratory and Altura Department of Human Genetics and 2 The Goldyne Savad Institute of Gene Therapy, Hadassah, Hebrew University Hospital, PO Box 12000, 91120 Jerusalem, Israel, 3 Department of Human Genetics, University of Chicago, 5841 S. Maryland MC6088, Chicago, IL, USA, 4 Alyn Hospital, PO Box 9117, 91090 Jerusalem, Israel and 5 Unit of Neuropediatrics and Child Development, Division of Pediatrics, Hadassah, Hebrew University Hospital, PO Box 12000, 91120 Jerusalem, Israel
* To whom correspondence should be addressed. Tel: +331 4959 1883; Fax: +331 4521 1940; Email: judith.melki{at}inserm.fr
Received May 19, 2009; Accepted June 16, 2009
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 Zmax = 3.55 at 
= 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.
Present address: Inserm Unit 788 and University of Paris 11, Bicetre Hospital, Gregory Pincus Building, 78 rue du Général Leclerc, Le Kremlin-Bicêtre 94275, France.
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