LRSAM1 variants and founder effect in French families with ataxic form of Charcot-Marie-Tooth type 2

• Published in: European journal of human genetics : EJHG Vol. 27; no. 9; pp. 1406 - 1418
• Main Authors: Peretti, Alessia, Perie, Maud, Vincent, Didier, Bouhour, Françoise, Dieterich, Klaus, Mallaret, Martial, Duval, Fanny, Goizet, Cyril, Juntas-Morales, Raul, Magy, Laurent, Solé, Guilhem, Nollet, Sylvain, Not, Adeline, Léonard-Louis, Sarah, Francou, Bruno, Leguern, Eric, Lia, Anne-Sophie, Magdelaine, Corinne, Latour, Philippe, Stojkovic, Tanya
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.09.2019; Springer International Publishing
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Alleles; Amino Acid Sequence; Amino acids; Ataxia; Autosomal dominant inheritance; Biopsy; Cell Cycle Proteins - genetics; Charcot-Marie-Tooth disease; Charcot-Marie-Tooth Disease - diagnosis; Charcot-Marie-Tooth Disease - genetics; Family; Founder Effect; France; Gene deletion; Genetic analysis; Genetic screening; Genetic Testing; Genetic Variation; Haplotypes; Heredity; Humans; Laboratories; Life Sciences; Localization; Neuropathy; Nuclear Proteins - genetics; Pedigree; Phenotype; Phenotypes; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - genetics; France
• ISSN: 1018-4813; 1476-5438; 1476-5438
• DOI: 10.1038/s41431-019-0403-8

Currently only 25-30% of patients with axonal forms of Charcot-Marie-Tooth disease (CMT) receive a genetic diagnosis. We aimed to identify the causative gene of CMT type 2 in 8 non-related French families with a distinct clinical phenotype. We collected clinical, electrophysiological, and laboratory findings and performed genetic analyses in four different French laboratories. Seventy-two patients with autosomal dominant inheritance were identified. The disease usually started in the fourth decade and the clinical picture was dominated by sensory ataxia (80%), neuropathic pain (38%), and length-dependent sensory loss to all modalities. Electrophysiological studies showed a primarily axonal neuropathy, with possible isolated sensory involvement in milder phenotypes. Disease severity varied greatly but the clinical course was generally mild. We identified 2 novel variants in LRSAM1 gene: a deletion of 4 amino acids, p.(Gln698_Gln701del), was found in 7 families and a duplication of a neighboring region of 10 amino acids, p.(Pro702_Gln711dup), in the remaining family. A common haplotype of ~450 kb suggesting a founder effect was noted around LRSAM1 in 4 families carrying the first variant. LRSAM1 gene encodes for an E3 ubiquitin ligase important for neural functioning. Our results confirm the localization of variants in its catalytic C-terminal RING domain and broaden the phenotypic spectrum of LRSAM1-related neuropathies, including painful and predominantly sensory ataxic forms.