Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy type 4B2/11p15

Abstract

Autosomal recessive hereditary motor and sensory neuropathy or Charcot-Marie-Tooth disease (CMT) is a severe childhood-onset neuromuscular disorder. Autosomal recessive CMT is genetically heterogeneous with one locus mapped to chromosome 11p15 (CMT4B2). The histopathological hallmarks of CMT4B2 are focal outfoldings of myelin in nerve biopsies. Homozygosity mapping, in a Turkish inbred family with four children affected by CMT characterized by focally folded myelin, provided linkage to the CMT4B2 locus. We identified a large, novel gene, named SET binding factor 2 (SBF2), that lies within this interval and is expressed in various tissues, including spinal cord and peripheral nerve. SBF2 is a member of the pseudo-phosphatase branch of myotubularins and was an obvious candidate for CMT4B2 by virtue of its striking homology to myotubularin-related protein 2 (MTMR2), causing another form of autosomal recessive CMT with outfoldings of the myelin sheaths. Molecular study of the SBF2 gene in the CMT4B family demonstrated the presence of a homozygous inframe deletion of SBF2 exons 11 and 12 in all four affected individuals. On the protein level, this mutation is predicted to disrupt an N-terminal domain that is conserved in SBF2 and its orthologues across species. Myotubularin-related proteins have been suggested to work in phosphoinositide-mediated signalling events that may also convey control of myelination. Localization of SBF2 within the candidate interval, cosegregation with the disease, expression in the peripheral nervous system, and resemblance of the histopathological phenotype to that related to mutations in its paralogue MTMR2 indicate that this gene is the CMT4B2 gene.

Phosphoinositide phosphatases in a network of signalling reactions

“…These mice showed a severe defect in maintaining mature myotubes. MTMR2 and MTMR13 are mutated in two forms of Charcot-Marie-Tooth Disease (CMT4B1 and CMT4B2, respectively), a neuropathy with defective myelination and myelin outfolding [13,113]. In MTMR2 knock-out mice, the myelin defect phenotype is also associated with impaired spermatogenesis and azoospermia [12].…”

Implication of phosphoinositide phosphatases in genetic diseases: the case of myotubularin

“…It has a 59 % amino acid identity with MTMR5/SBF1 and has the cysteine from its phosphatase site replaced by a leucine, which predicts an abolished lipid phosphatase activity. The gene for SBF2 was located to chromosome 11p15 by linkage analysis and found mutated in cases of autosomal recessive Charcot-Marie-Tooth disease CMT4B2 with focally folded myelin (OMIM 604563) associated with early-onset glaucoma [114,115]. This is the first report of an inactive phosphatase mutated in a human genetic disease.…”

Autosomal recessive demyelinating or axonal Charcot–Marie–Tooth neuropathy

“…This was demonstrated in consanguineous Tunisian families by absence of linkage to the 11q22 locus, and subsequent mapping to chromosome 11p15 [44]. The gene responsible for CMT4B2 encodes the SET binding factor 2 (SBF2) [45], also called the myotubularin-related protein 13 (MTMR13) [46].…”

“…Years after disease onset, progression to proximal weakness with loss of ambulation occurs in some patients. Severe distal sensory loss, absent deep tendon reflexes in the legs, reduced reflexes in the arms, pes cavus, and hammer toes were noted in CMT4B2 patients [44][45][46]. In some families, the CMT4B2 phenotype segregates with a congenital or juvenile-onset glaucoma [46][47][48].…”