Mutations in MTMR13, a New Pseudophosphatase Homologue of MTMR2 and Sbf1, in Two Families with an Autosomal Recessive Demyelinating Form of Charcot-Marie-Tooth Disease Associated with Early-Onset Glaucoma

Abstract

Charcot-Marie-Tooth disease (CMT) with autosomal recessive (AR) inheritance is a heterogeneous group of inherited motor and sensory neuropathies. In some families from Japan and Brazil, a demyelinating CMT, mainly characterized by the presence of myelin outfoldings on nerve biopsies, cosegregated as an autosomal recessive trait with early-onset glaucoma. We identified two such large consanguineous families from Tunisia and Morocco with ages at onset ranging from 2 to 15 years. We mapped this syndrome to chromosome 11p15, in a 4.6-cM region overlapping the locus for an isolated demyelinating ARCMT (CMT4B2). In these two families, we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13. The MTMR protein family includes proteins with a phosphoinositide phosphatase activity, as well as proteins in which key catalytic residues are missing and that are thus called "pseudophosphatases." MTM1, the first identified member of this family, and MTMR2 are responsible for X-linked myotubular myopathy and Charcot-Marie-Tooth disease type 4B1, an isolated peripheral neuropathy with myelin outfoldings, respectively. Both encode active phosphatases. It is striking to note that mutations in MTMR13 also cause peripheral neuropathy with myelin outfoldings, although it belongs to a pseudophosphatase subgroup, since its closest homologue is MTMR5/Sbf1. This is the first human disease caused by mutation in a pseudophosphatase, emphasizing the important function of these putatively inactive enzymes. MTMR13 may be important for the development of both the peripheral nerves and the trabeculum meshwork, which permits the outflow of the aqueous humor. Both of these tissues have the same embryonic origin.

Membrane association of myotubularin-related protein 2 is mediated by a pleckstrin homology-GRAM domain and a coiled-coil dimerization module

“…6 for review), which is characterized by reduced nerve conduction velocity and focally folded myelin sheets in peripheral nerves (7). Mutations in sbf2͞MTMR13 lead to a disease with identical pathology in the peripheral nervous system called CMT4B2, and are associated with early onset glaucomas in some families (8,9). Mutations in MTM (MTM1), the founding member of the family, lead to X-linked myotubular myopathy (10).…”

Characterization of myotubularin-related protein 7 and its binding partner, myotubularin-related protein 9

“…Mutations in myotubularin 1 (MTM1) cause the disorder as identified by positional cloning (1). At least 13 MTM1-like proteins have been found in the human genome, and they are termed MTM-related proteins (MTMRs) (2)(3)(4). MTMR2 is mutated in a recessive form of Charcot-Marie-Tooth disease type 4B, a demyelinating neurological disorder (5).…”

Fenótipos Raros de Neuropatia Hereditária: Charcot-Marie-Tooth Tipo 4

“…A Doença de Charcot-Marie-Tooth tipo 4B2 é causada por mutações no gene MTMR13/SBF2 no cromossomo 11p15, uma pseudofosfatase e miotubularina (homóloga de MTMR2 e SBF1), envolvida no tráfico de vesículas nas células de Schwann, que controlam a mielinização 36,37 .…”

“…Caracteriza-se por ser uma neuropatia sensitivo-motora com início na primeira ou na segunda década de vida e que inclui início precoce de glaucoma. As deficiências visuais são resultados desse glaucoma congênito com buftalmia, megalocórnea e aumento da pressão intraocular 36 .…”