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.

The LINC complex is essential for hearing

“…For example, mutations in SYNE1, which encodes a protein expressed mainly in the cerebellum, have been implicated in autosomal recessive cerebellar ataxia (32). Mutations in the same gene are predicted to lead to an autosomal recessive form of myogenic arthrogryposis multiplex congenita (AMC) (33). Emery-Dreifuss muscular dystrophy-5 (EDMD5) patients, with late onset neuromuscular disorders, harbor mutations in both SYNE1 and SYNE2 (34).…”

Nuclear alignment in myotubes requires centrosome proteins recruited by nesprin-1

“…In particular, mutations in these proteins have been reported in human patients and in mouse models with EmeryDreifuss muscular dystrophy, as well as ataxias and cardiomyopathies (Ellis, 2006;Gros-Louis et al, 2007;Wheeler et al, 2007;Zhang et al, 2007a;Attali et al, 2009;Puckelwartz et al, 2009Puckelwartz et al, , 2010. It has been speculated that these mutations might affect signalling pathways in muscle cells, but the exact role of nuclear envelope components in myopathies remains unclear.…”

The Nuclear Envelope: An Intriguing Focal Point for Neurogenetic Disease

“…Mutations and polymorphisms in SYNE1 and SYNE2 genes, which respectively encode the KASH domain proteins nesprin-1 and nesprin-2, have also been reported in patients with muscular dystrophy and cardiomyopathy; disruption of the orthologous genes in mice causes skeletal and cardiac myopathy [49][50][51][52]. A mutation in SYNE1 has also been linked to an autosomal recessive form of arthrogryposis multiplex congenita, a syndrome of congenital joint contractures that results from reduced fetal movement [53]. A mutation in TOR1AIP1 encoding LAP1 has been described in two affected family members in with muscular dystrophy and cardiomyopathy [54].…”