Autosornal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths

Quattrone, Aldo; Gambardella, Antonio; Bono, Francesco; Aguglia, Umberto; Bolino, Alessandra; Bruni, Amalia C.; Montesi, M. P.; Oliveri, R. L.; Sabatelli, Mario; Tamburrini, O; Valentino, Paola; Broeckhoven, Christine Van; Zappia, Mario

doi:10.1212/wnl.46.5.1318

Cited by 106 publications

(89 citation statements)

References 32 publications

(2 reference statements)

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“…These disorders involve optic nerves, 30 phrenic and vagal nerves, 31 facial and vestibular nerves, 16 trigeminal nerve, 32 and auditory nerve. [33][34][35] Other sensory nerve involvement (olfaction and taste) has not been specifically commented on. The results of the genetic analysis for the Slovenian family combined with the results for the Bulgarian and Italian families 9,11 suggest that the region of chromosome 8 containing the disease locus can be refined to the interval between 189CA17 and D8S256.…”

Section: Arrows) Onion Bulb Formations Are Not Evident (Paraphenylinmentioning

confidence: 99%

Hereditary auditory, vestibular, motor, and sensory neuropathy in a Slovenian Roma (Gypsy) kindred

et al. 1999

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Members of a Roma (Gypsy) family with hereditary motor and sensory peripheral neuropathy (HMSN) and concomitant auditory and vestibular cranial neuropathies were identified in Kocevje, Slovenia. The illness begins in childhood with a severe and progressive motor disability and the deafness is delayed until the second decade. There are no symptoms of vestibular dysfunction. The family structure is consistent with an autosomal recessive pattern of inheritance and the genetic locus for the disorder is linked to the same region of chromosome 8q24 as other Roma families with HMSN and deafness from Lom, Bulgaria (HMSN‐Lom). The present study shows that the deafness is caused by a neuropathy of the auditory nerve with preserved measures of cochlear outer hair cell function (otoacoustic emissions and cochlear microphonics) but absent neural components of auditory brainstem potentials. The hearing loss affects speech comprehension out of proportion to the pure tone loss. Vestibular testing showed absence of caloric responses. Physiological and neuropathological studies of peripheral nerves were compatible with the nerve disorder contemporaneously affecting Schwann cells and axons resulting in both slowed nerve conduction and axonal loss. Genetic linkage studies suggest a refinement of the 8q24 critical region containing the HMSN‐Lom locus that affects peripheral motor and sensory nerves as well as the cranial auditory and vestibular nerves. Ann Neurol 1999;46:36–44

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Section: Arrows) Onion Bulb Formations Are Not Evident (Paraphenylinmentioning

confidence: 99%

Hereditary auditory, vestibular, motor, and sensory neuropathy in a Slovenian Roma (Gypsy) kindred

et al. 1999

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“…The disease is characterized by onset in early childhood with symmetrical distal and proximal muscle weakness. Adult patients are seriously handicapped and wheelchair-bound (1). Although clinically homogenous, two different gene loci have been identified for CMT4B (2).…”

Section: Introductionmentioning

confidence: 99%

Loss of Phosphatase Activity in Myotubularin‐related Protein 2 is Associated with Charcot‐marie‐tooth Disease Type 4B1

Berger

Bonneick

Willi

et al. 2003

J Peripheral Nervous Sys

109

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Mutations in the gene encoding myotubularin-related protein 2 (MTMR2) are responsible for autosomal recessive Charcot-Marie-Tooth disease type 4B1 (CMT4B1), a severe hereditary motor and sensory neuropathy characterized by focally folded myelin sheaths and demyelination. MTMR2 belongs to the myotubularin family, which is characterized by the presence of a phosphatase domain. Myotubularin (MTM), the archetype member of this family, is mutated in X-linked myotubular myopathy. Although MTMR2 and MTM are closely related, they are likely to have different functions. Recent studies revealed that MTM dephosphorylates specifically phosphatidylinositol 3-phosphate. Here we analyze the biochemical properties of the mouse Mtmr2 protein, which shares 97% amino acid identity with human MTMR2. We show that phosphatidylinositol-3-phosphate is also a substrate for Mtmr2, but, unlike myotubularin, Mtmr2 dephosphorylates phosphatidylinositol 3,5-bisphosphate with high efficiency and peak activity at neutral pH. We demonstrate that the known disease-associated MTMR2 mutations lead to dramatically reduced phosphatase activity, suggesting that the MTMR2 phosphatase activity is crucial for the proper function of peripheral nerves in CMT4B1. Expression analysis of Mtmr2 suggests particularly high levels in neurons. Thus, the demyelinating neuropathy CMT4B1 might be triggered by the malfunction of neural membrane recycling, membrane trafficking, and/or endocytic or exocytotic processes, combined with altered axon-Schwann cell interactions. Furthermore, the different biochemical properties of MTM and MTMR2 offer a potential explanation for the different human diseases caused by mutations in their respective genes.

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“…2-5; see ref. 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).…”

mentioning

confidence: 99%

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

Berger¹,

Schaffitzel²,

Berger³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

104

128

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Mutations in the myotubularin (MTM)-related protein 2 (MTMR2) gene are responsible for the severe autosomal recessive neuropathy Charcot-Marie-Tooth disease type 4B1. MTMR2 belongs to the MTM family of dual-specific phosphatases that use phosphatidylinositol (PI) 3,5-bisphosphate [PI(3,5)P 2] and PI 3-phosphate [PI(3)P] as their substrate. Because these substrates are localized in the membrane bilayer, membrane targeting of Mtmr2 is an important regulatory mechanism. In hypoosmotically stressed COS cells with increased levels of PI(3,5)P 2, Mtmr2 is bound to the membrane of vacuoles formed under these conditions. Using several mutant forms of Mtmr2, we identified two domains that are necessary for membrane association: (i) A pleckstrin homology-GRAM domain; and (ii) a coiled-coil module. Protein-lipid overlay assays show that the pleckstrin homology-GRAM domain binds to PI(3,5)P 2 and PI(5)P, a substrate and a product of the Mtmr2 enzyme, respectively. We also demonstrate that Mtmr2 forms a dimer and that the C-terminal coiled-coil is responsible for homodimerization, in addition to membrane association. Our data indicate that phosphoinositide-protein interactions, as well as protein-protein interactions, are necessary for the correct regulation of MTMR2.

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Autosornal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths

Cited by 106 publications

References 32 publications

Hereditary auditory, vestibular, motor, and sensory neuropathy in a Slovenian Roma (Gypsy) kindred

Hereditary auditory, vestibular, motor, and sensory neuropathy in a Slovenian Roma (Gypsy) kindred

Loss of Phosphatase Activity in Myotubularin‐related Protein 2 is Associated with Charcot‐marie‐tooth Disease Type 4B1

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

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