A frameshift mutation in LRSAM1 is responsible for a dominant hereditary polyneuropathy

Abstract

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.

A LRSAM1 mutation links Charcot–Marie–Tooth type 2 to Parkinson's disease

“…Recently, members of our group identified a frameshift mutation in LRSAM1 as the cause of dominantly inherited, axonal sensorimotor neuropathy in a Dutch family (Charcot–Marie–Tooth, CMT, type 2P) 1. This finding was confirmed by others,2, 3 and another homozygous mutation in this gene was previously found in a recessive CMT family (AR‐CMT2P) 4.…”

“…LRSAM1 encodes a multifunctional protein and is expressed in the fetal and adult nervous system 1. Its ubiquitylating capacity was shown to be perturbed as a result of the Dutch mutation.…”

“…This raises intriguing questions regarding the endogenous LRSAM1 targets and seems to link processes of mitochondrial dynamics and autophagy. Animal models have proven that LRSAM1 mutations cause neurological disease in mouse and zebrafish 1, 8. In this respect, it is interesting to note that lrsam1 −/− mice when challenged with acrylamide showed poor coordination and tremor 8.…”

“…As described in the original paper,1 all family members affected by CMT2, including the three with concomitant PD, were carrying a frameshift mutation (c.2121_2122insGC; p.Leu708Argfx28) in the LRSAM1 gene. In addition, we excluded mutations in other genes that are associated with genetic forms of parkinsonism in subject 2.4 ( SNCA , parkin , PINK1 , DJ‐1 , GBA , POLG , VPS35 , DNAJC13 , LRRK2 , ATXN2 , ATXN3 , C ACNA1A , TBP , and ATN1) .…”

A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease

“…17 Recently, two novel LRSAM1 mutations were associated with axonal CMT neuropathies. 18,19 The p.Glu638AlafsX7 mutation has been reported in a family with AR axonal CMT and the p.Leu708ArgfsX28 mutation has been identified in a family with AD axonal CMT (CMT2). The leucine-rich repeat and sterile alpha motif-containing 1 (LRSAM1) protein is a RING finger protein with multiple functions that has a role in receptor endocytosis.…”