Genotype-Phenotype Correlations in Charcot-Marie-Tooth Disease Due to MTMR2 Mutations and Implications in Membrane Trafficking

Abstract

Charcot-Marie-Tooth type 4 (CMT4) is an autosomal recessive severe form of neuropathy with genetic heterogeneity. CMT4B1 is caused by mutations in the myotubularin-related 2 (MTMR2) gene and as a member of the myotubularin family, the MTMR2 protein is crucial for the modulation of membrane trafficking. To enable future clinical trials, we performed a detailed review of the published cases with MTMR2 mutations and describe four novel cases identified through whole-exome sequencing (WES). The four unrelated families harbor novel homozygous mutations in MTMR2 (NM_016156, Family 1: c.1490dupC; p.Phe498IlefsTer2; Family 2: c.1479+1G>A; Family 3: c.1090C>T; p.Arg364Ter; Family 4: c.883C>T; p.Arg295Ter) and present with CMT4B1-related severe early-onset motor and sensory neuropathy, generalized muscle atrophy, facial and bulbar weakness, and pes cavus deformity. The clinical description of the new mutations reported here overlap with previously reported CMT4B1 phenotypes caused by mutations in the phosphatase domain of MTMR2, suggesting that nonsense MTMR2 mutations, which are predicted to result in loss or disruption of the phosphatase domain, are associated with a severe phenotype and loss of independent ambulation by the early twenties. Whereas the few reported missense mutations and also those truncating mutations occurring at the C-terminus after the phosphatase domain cause a rather mild phenotype and patients were still ambulatory above the age 30 years. Charcot-Marie-Tooth neuropathy and Centronuclear Myopathy causing mutations have been shown to occur in proteins involved in membrane remodeling and trafficking pathway mediated by phosphoinositides. Earlier studies have showing the rescue of MTM1 myopathy by MTMR2 overexpression, emphasize the importance of maintaining the phosphoinositides equilibrium and highlight a potential compensatory mechanism amongst members of this pathway. This proved that the regulation of expression of these proteins involved in the membrane remodeling pathway may compensate each other's loss- or gain-of-function mutations by restoring the phosphoinositides equilibrium. This provides a potential therapeutic strategy for neuromuscular diseases resulting from mutations in the membrane remodeling pathway.

A CRISPR screen in intestinal epithelial cells identifies novel factors for polarity and apical transport

“…Finally, it should be noted that several genes identified in our screening have been associated with neuropathies or myopathies (Charcot–Marie–Tooth syndrome [MTMR2]; Dyggve–Melchior–Clausen syndrome [DYM]) ( Denais et al, 2011 ; Wang et al, 2019 ). Thus, it would be worthwhile to examine our dataset in the context of other cellular systems as defective secretory transport and cellular polarization provide a mechanistic basis for a spectrum of pathologies in many tissues and organs.…”

Pathology of the peripheral neuropathy Charcot-Marie-Tooth disease type 4H in Holstein Friesian cattle with a splice site mutation in FGD4

“…39 Indeed, humans with MTMR2 mutations and CMT4B1 also have myelin outfoldings. 16,42 Therefore, the myelin outfoldings are suggested to result from dysregulation of the cytoskeleton and membrane transport processes, such as endocytosis, due to impaired Rho GTPase signaling. 38,39 In summary, cattle homozygous for the FGD4 mutation, despite not having severe clinical signs, had lesions on semithin sections and electron microscopy consistent with CMT4H in humans and mouse models.…”

“…39 Indeed, humans with MTMR2 mutations and CMT4B1 also have myelin outfoldings. 16,42 Therefore, the myelin outfoldings are suggested to result from dysregulation of the cytoskeleton and membrane transport processes, such as endocytosis, due to impaired Rho GTPase signaling. 38,39…”

Identification of a Novel Homozygous Mutation in MTMR2 Gene Causes Very Rare Charcot–Marie–Tooth Disease Type 4B1

“… 5 , 15 MTMR2 associated CMT4B1 is a rarely reported form of muscular dystrophy, and the genotype-phenotype correlation has also been recently investigated. 4 , 12 , 16 To date, no therapeutic treatment has been developed for patients with CMT4B1. 17–20 …”