Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction

Abstract

Background Charcot-Marie-Tooth disease (CMT) type 4B3 (CMT4B3) is a rare form of genetic neuropathy associated with variants in the MTMR5/SBF1 gene. MTMR5/SBF1 is a pseudophosphatase predicted to regulate endo-lysosomal trafficking in tandem with other MTMRs. Although almost ubiquitously expressed, pathogenic variants primarily impact on the peripheral nervous system, corroborating the involvement of MTMR5/SBF1 and its molecular partners in Schwann cells-mediated myelinization. Case presentation We report a case of severe CMT4B3 characterized by early-onset motor and axonal polyneuropathy in an Italian child in absence of any evidence of brain and spine MRI abnormalities or intellectual disability and with a biochemical profile suggestive of mitochondrial disease. Using an integrated approach combining both NGS gene panels and WES analysis, we identified two novel compound heterozygous missense variants in MTMR5/SBF1 gene, p.R763H (c.2291G > A) and p.G1064E (c.3194G > A). Studies in muscle identified partial defects of oxidative metabolism. Conclusion We describe the first case of an early onset severe polyneuropathy with motor and axonal involvement, due to recessive variants in the MTMR5/SBF1 gene, with no evidence of brain and spine MRI abnormalities, intellectual disability, no clinical and neurophysiological evidences of distal sensory impairment, and rapid neuromuscular deterioration. This report suggests that MTMR5/SBF1 should be considered in cases of infantile-onset CMT with secondary mitochondrial dysfunction.

A (GCC) repeat in SBF1 reveals a novel biological phenomenon in human and links to late onset neurocognitive disorder

“…SBF1 is predominantly expressed in the brain and skeletal muscle, and the protein encoded by this gene is a member of the myotubularin family. Myotubularin-related proteins, namely MTMR2, MTMR13/SBF2 and MTMR5/SBF1 are mainly involved in regulating endolysosomal trafficking 33 and mitochondrial functioning 34 . Dysregulation of SBF1 is linked to late-onset NCDs such as AD 17 , which is also indicated by the observed genotype anomalies in the NCD group versus controls in our study.…”

Genetic determinants of taxane-induced peripheral neuropathy

“…SBF2 gene mutations are associated with the development of the Charcot-Marie-Tooth subtype of disease that manifests as an inherited form of polyneuropathy. The almost exclusive involvement of the peripheral nervous system observed in the Charcot-Marie-Tooth 4B subtype, in which the MTMR13/SBF2 genes are essential, suggests that the Schwann cells are sensitive to the disruption of endolysosomal trafficking, which may be affected specifically by SBF2 polymorphisms (40).…”

Characterization of a novel zebrafish model ofMTMR5-associated CMT4B3

“…CMT4B3 is unique as compared to CMT4B1/2 because patients experience signs and symptoms unrelated to peripheral demyelination. These unique clinical features include axonal peripheral neuropathy (Gang et al, 2020), structural brain changes (fork and bracket syndrome) (Romani et al, 2016), intellectual disability (Berti et al, 2021), and alterations in skeletal muscle. The expanded phenotype of CMT4B3 suggests that MTMR5 has functions beyond those specifically related to MTMR2, and also that therapies targeted at CMT4B1/2 may not fully address critical aspects of the CMT4B3 clinical syndrome.…”

“…Of note, the presence of N-terminal DENN domains is a unique feature of MTMR5 and MTMR13 in the myotubularin family (Laporte et al, 2003). Whilst missense CMT4B3 patient variants (Mégarbané et al, 2010, Nakhro et al, 2013, Alazami et al, 2014, Manole et al, 2016, Romani et al, 2016, Flusser et al, 2018, Gang et al, 2020, Berti et al, 2021) are clustered in the DENN domains and the SBF2 domain (Fig. 1A), suggesting their importance in normal function of MTMR5, pathogenic variants are reported throughout the gene (Landrum et al, 2020), and are associated with loss of expression and/or function (see Supplementary Table 1 for detailed information on the pathogenic variants).…”