Journal Article

A frameshift mutation in <i>LRSAM1</i> is responsible for a dominant hereditary polyneuropathy

Marian A.J. Weterman, Vincenzo Sorrentino, Paul R. Kasher, Marja E. Jakobs, Baziel G.M. van Engelen, Kees Fluiter, Marit B. de Wissel, Aleksander Sizarov, Gudrun Nürnberg, Peter Nürnberg, Noam Zelcer, H. Jurgen Schelhaas and Frank Baas

in Human Molecular Genetics

Volume 21, issue 2, pages 358-370
Published in print January 2012 | ISSN: 0964-6906
Published online October 2011 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddr471
A frameshift mutation in LRSAM1 is responsible for a dominant hereditary polyneuropathy

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Despite the high number of genes identified in hereditary polyneuropathies/Charcot–Marie–Tooth (CMT) disease, the genetic defect in many families is still unknown. Here we report the identification of a new gene for autosomal dominant axonal neuropathy in a large three-generation family. Linkage analysis identified a 5 Mb region on 9q33–34 with a LOD score of 5.12. Sequence capture and next-generation sequencing of the region of interest identified five previously unreported non-synonymous heterozygous single nucleotide changes or indels, four of which were confirmed by Sanger sequencing. Two sequence variants co-segregated with the disease, and one, a 2 bp insertion in the last exon of LRSAM1, was also absent in 676 ethnicity-matched control chromosomes. This frameshift mutation (p.Leu708Argfx28) is located in the C-terminal RING finger motif of the encoded protein. Ubiquitin ligase activity in transfected cells with constructs carrying the patient mutation was affected as measured by a higher level of abundance of TSG101, the only reported target of LRSAM1. Injections of morpholino oligonucleotides in zebrafish embryos directed against the ATG or last splice site of zebrafish Lrsam1 disturbed neurodevelopment, showing a less organized neural structure and, in addition, affected tail formation and movement. LRSAM1 is highly expressed in adult spinal cord motoneurons as well as in fetal spinal cord and muscle tissue. Recently, a homozygous mutation in LRSAM1 was proposed as a strong candidate for the disease in a family with recessive axonal polyneuropathy. Our data strongly support the hypothesis that LRSAM1 mutations can cause both dominant and recessive forms of CMT.

Journal Article.  7076 words.  Illustrated.

Subjects: Genetics and Genomics

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