Inherited demyelinating peripheral neuropathies: Relating myelin packing abnormalities to P0 molecular defects

Kirschner, Daniel A.; Szumowski, K.; Gabreëls-Festen, A.A.W.M.; Hoogendijk, Jessica E.; Bolhuis, P. A.

doi:10.1002/(sici)1097-4547(19961115)46:4<502::aid-jnr12>3.0.co;2-#

Cited by 31 publications

(17 citation statements)

References 20 publications

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“…Sequencing of the PCR products from exon two of two affected members and one control indicated a heterozygous change from GAC to TAC (aspartate to tyrosine) at codon 35 of the cDNA (numbered according to the Human Gene Mutation Database35) (fig 3). Codon 35 is the equivalent of amino acid 6 of the processed protein15 36 and the inferred amino acid change may therefore be designated Asp6Tyr. Polymerase chain reaction products of exon 2 from all 10 affected members amplified using the mismatch primer which introduces an Alu I site when the mutation is present, showed a smaller, 171 bp product, after Alu I digestion.…”

Section: Resultsmentioning

confidence: 99%

Novel mutation in the myelin protein zero gene in a family with intermediate hereditary motor and sensory neuropathy

Mastaglia

Nowak

Stell

et al. 1999

Journal of Neurology, Neurosurgery & Psychiatry

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Objectives-To determine the molecular basis for autosomal dominant intermediate hereditary motor and sensory neuropathy (HMSN) in a four generation family. The gene defects in families with intermediate HMSN are not known, but it has been suggested that most have X linked HMSN. Methods-All participating family members were examined clinically. Genomic DNA was obtained from 10 aVected and seven unaVected members. Linkage analysis for the known HMSN loci was first performed. Mutations in the peripheral myelin protein zero gene (PMP0) were sought in two aVected members, using one unaVected member for comparison, by amplification of the six exons of the gene followed by single strand conformation polymorphism (SSCP) analysis, dideoxy fingerprinting (ddF), and sequencing. Subsequently, the mutation was screened for in all aVected and unaVected members in the family using Alu I digestion and in 100 unrelated control subjects using "snap back" SSCP analysis. Sequencing of cDNA from a sural nerve biopsy from an aVected member was also performed. Results-The clinical phenotype was of variable severity, with motor nerve conduction velocities in the intermediate range. Linkage to PMP0 was demonstrated. Analysis of genomic DNA and cDNA for PMP0 identified a novel codon 35 GAC to TAC mutation. The mutation produces an inferred amino acid change of aspartate to tyrosine at codon six of the processed protein (Asp6Tyr) in the extracellular domain and was present in all aVected family members but not in 100 unrelated controls. Conclusions-The present findings further extend the range of phenotypes associated with PMP0 mutations and indicate that families with "intermediate" HMSN need not necessarily be X-linked as previously suggested. (J Neurol Neurosurg Psychiatry 1999;67:174-179)

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Section: Resultsmentioning

confidence: 99%

Novel mutation in the myelin protein zero gene in a family with intermediate hereditary motor and sensory neuropathy

Mastaglia

Nowak

Stell

et al. 1999

Journal of Neurology, Neurosurgery & Psychiatry

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“…Specific packing defects in the myelin intraperiod line have been detected in CMT1B as a result of extracellular domain mutations (e.g., R98H, R98C) (Kirschner et al, 1996), suggesting that the mutant proteins are synthesized and inserted into the myelin sheath. When cotransfected with wild-type P0, either P0 truncated in the cytoplasmic domain or P0 unable to form a disulfide bond in the extracellular domain impaired the adhesion of wild-type P0 between Chinese hamster ovary cells, suggesting a dominantnegative gain of function effect (Wong and Filbin, 1996;Zhang and Filbin, 1998).…”

Section: Both S63 Mutants Produce Gain Of Function Mechanismsmentioning

confidence: 89%

Different Intracellular Pathomechanisms Produce DiverseMyelin Protein ZeroNeuropathies in Transgenic Mice

Wrabetz¹,

D’Antonio²,

Pennuto³

et al. 2006

J. Neurosci.

146

263

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Missense mutations in 22 genes account for one-quarter of Charcot-Marie-Tooth (CMT) hereditary neuropathies. Myelin Protein Zero (MPZ, P0) mutations produce phenotypes ranging from adult demyelinating (CMT1B) to early onset [Déjérine-Sottas syndrome (DSS) or congenital hypomyelination] to predominantly axonal neuropathy, suggesting gain of function mechanisms. To test this directly, we produced mice in which either the MpzS63C (DSS) or MpzS63del (CMT1B) transgene was inserted randomly, so that the endogenous Mpz alleles could compensate for any loss of mutant P0 function. We show that either mutant allele produces demyelinating neuropathy that mimics the corresponding human disease. However, P0S63C creates a packing defect in the myelin sheath, whereas P0S63del does not arrive to the myelin sheath and is instead retained in the endoplasmic reticulum, where it elicits an unfolded protein response (UPR). This is the first evidence for UPR in association with neuropathy and provides a model to determine whether and how mutant proteins can provoke demyelination from outside of myelin.

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“…According to a molecular model for the extramembraneous part of the protein, amino acid 122 should be located at the base of the molecule close to the Schwann cell membrane 12. The phenotype associated with this mutation was mild with late onset with NCVs between 20 and 40 m/s.…”

Section: Discussionmentioning

confidence: 99%

Axonal phenotype of Charcot-Marie-Tooth disease associated with a mutation in the myelin protein zero gene

Chapon¹,

Latour

Diraison

et al. 1999

Journal of Neurology, Neurosurgery & Psychiatry

112

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A French family had Charcot-Marie-Tooth disease type 2 (CMT2) which was characterised by late onset of peripheral neuropathy involvement, Argyll Robertsonlike pupils, dysphagia, and deafness. Electrophysiological studies and nerve biopsy defined the neuropathy as axonal type. Genetic analysis of myelin protein zero (MPZ) found a mutation in codon 124 resulting in substitution of threonine by methionine. One of the patients, presently 30 years old, showed only Argyll Robertson-like pupils as an objective sign but no clinical or electrophysiological signs of peripheral neuropathy. (J Neurol Neurosurg Psychiatry 1999;66:779-782)

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Inherited demyelinating peripheral neuropathies: Relating myelin packing abnormalities to P0 molecular defects

Cited by 31 publications

References 20 publications

Novel mutation in the myelin protein zero gene in a family with intermediate hereditary motor and sensory neuropathy

Novel mutation in the myelin protein zero gene in a family with intermediate hereditary motor and sensory neuropathy

Different Intracellular Pathomechanisms Produce DiverseMyelin Protein ZeroNeuropathies in Transgenic Mice

Axonal phenotype of Charcot-Marie-Tooth disease associated with a mutation in the myelin protein zero gene

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