Human Molecular Genetics Advance Access published online on June 19, 2009
Human Molecular Genetics, 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, Hadassah, Hebrew University Hospital, PO Box 12000, 91120 Jerusalem, Israel 2 The Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital 3 Department of Human Genetics, the University of Chicago, 5841 S. Maryland, MC6088, Chicago 4 Alyn Hospital, POB 9117, Jerusalem 91090 5 The Unit of Neuropediatrics and Child Development, Division of Pediatrics, Hadassah, Hebrew University Hospital
* Correspondence should be addressed to Judith Melki. 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. Tel: 331 4959 1883; FAX: 331 4521 1940; e-mail: judith.melki{at}inserm.fr
Received May 19, 2009; Revised June 16, 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 3,000 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 neurologic, a feature similar to that found in laminopathies.
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  J. Zhang, A. Felder, Y. Liu, L. T. Guo, S. Lange, N. D. Dalton, Y. Gu, K. L. Peterson, A. P. Mizisin, G. D. Shelton, et al. Nesprin 1 is critical for nuclear positioning and anchorage Hum. Mol. Genet., November 9, 2009; (2009) ddp499v2. [Abstract] [Full Text] [PDF]
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