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

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...

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Published in:European journal of human genetics : EJHG 2019-09, Vol.27 (9), p.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: Article
Language:English
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
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Summary: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.
ISSN:1018-4813
1476-5438
1476-5438
DOI:10.1038/s41431-019-0403-8