A frame shift mutation in the PMP22 gene in hereditary neuropathy with liability to pressure palsies

Nicholson, Garth A.; Valentijn, Linda J.; Cherryson, A.K.; Kennerson, Marina; Bragg, T.; DeKroon, Robert M.; Ross, David A.; Pollard, John D.; McLeod, J. G.; Bolhuis, P. A.; Baas, Frank

doi:10.1038/ng0394-263

Cited by 202 publications

(110 citation statements)

References 23 publications

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“…A decreased dosage of PMP22 is a possible cause of HNPP. This hypothesis is supported by the fact that a nondeleted HNPP patient was identified who carried a 2-bp deletion in PMP22 causing early ter mination of transcription [35].…”

Section: Introductionsupporting

confidence: 58%

Estimation of the Mutation Frequencies in Charcot-Marie-Tooth Disease Type 1 and Hereditary Neuropathy with Liability to Pressure Palsies: A European Collaborative Study

Nelis

Broeckhoven

Mariman³

et al. 1996

Eur J Hum Genet

387

223

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A European collaboration on Charcot-Marie-Tooth type 1 (CMT1) disease and hereditary neuropathy with liability to pressure palsies (HNPP) was estab lished to estimate the duplication and deletion frequency, respectively, on chromosome 17pl 1.2 and to make an inventory of mutations in the myelin genes, peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) and connexin 32 (Cx32) located on chromosomes 17pl 1.2, Iq21-q23 andXql3.1, respectively. In 70.7% of 819 unrelated CMT1 patients, the 17p11.2 duplica tion was present. In 84.0% of 156 unrelated HNPP patients, the 17p 11.2 dele tion was present. In the nonduplicated CMT1 patients, several different muta tions were identified in the myelin genes PMP22, MPZ and Cx32.

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Section: Introductionsupporting

confidence: 58%

Estimation of the Mutation Frequencies in Charcot-Marie-Tooth Disease Type 1 and Hereditary Neuropathy with Liability to Pressure Palsies: A European Collaborative Study

Nelis

Broeckhoven

Mariman³

et al. 1996

Eur J Hum Genet

387

223

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“…sociated with HNPP disease, where one copy of the gas3~ PMP22 locus on a homologous chromosome 17 is deleted (Nicholson et al 1994). On the contrary, in the heterozygous condition T118M-carrying individuals are asymptomatic (Roa et al 1993b).…”

Section: Genes and Developmentmentioning

confidence: 99%

Apoptotic phenotype induced by overexpression of wild-type gas3/PMP22: its relation to the demyelinating peripheral neuropathy CMT1A.

Fabbretti

Edomi²,

Brancolini³

et al. 1995

Genes Dev.

178

141

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Although the Gas3/PMP22 protein is expressed at highest levels in differentiated Schwann cells, its presence, albeit at lower levels, in non-neuronal tissues and in NIH-3T3 growth-arrested fibroblasts argues for a more general function of this protein that is uncoupled to myelin structure. We show that gas3/PMP22 overexpression in NIH-3T3 growing cells leads to an apoptotic-like phenotype, which is suppressed by antioxidants and characterized by typical membrane blebbing, rounding up, and chromatin condensation, but with no evidence of DNA fragmentation. REF-52 fibroblasts seem to be completely refractive to gas3/PMP22 overexpression. Recently, several point mutations of the human gas3/PMP22 gene have been associated with Charcot-Marie-Tooth type 1A (CMT1A), a common hereditary demyelinating neuropathy. When gas3/PMP22 point mutations (L16P, $79C, TllSM, and G150D) are similarly overexpressed in NIH-3T3 cells, the induced apoptotic-like phenotype as compared to the wild-type is significantly reduced. Both of the dominant mutations (L16P, $79C~ for CMT1A behave as dominant negatives with respect to the wild type, whereas Tl18M, the only recessive mutant described, behaves as recessive under the same coexpression experiments.These data suggest a role for altered Schwann cell apoptosis in the pathogenesis of CMT1A.

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“…Alternatively, other PMP22 mutations have been reported to cause a typical HNPP phenotype. These include Leu4Ter,9 Leu7 fs,10, 11 Gly94 fs,12, 23 Tyr97 fs,24 and Thr99 fs25 PMP22 . Mutations that cause an HNPP phenotype eliminate the mutant allele by processes such as nonsense‐mediated decay 11, 26.…”

Section: Discussionmentioning

confidence: 99%

“…Most CMT1E mutations are missense mutations probably resulting in a gain‐of‐new protein function 8. In contrast, some PMP22 point mutations produce a loss‐of‐protein function by a shift in the protein reading frame, leading to premature termination of translation 9, 10, 11, 12. A similar loss of function can also be caused by the reciprocal deletion of PMP22 within 17p12 that caused the CMT1A duplication.…”

Section: Introductionmentioning

confidence: 99%

PMP22 exon 4 deletion causes ER retention of PMP22 and a gain‐of‐function allele in CMT1E

Wang

Bai

et al. 2017

Ann Clin Transl Neurol

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ObjectiveTo determine whether predicted fork stalling and template switching (FoSTeS) during mitosis deletes exon 4 in peripheral myelin protein 22 KD (PMP22) and causes gain‐of‐function mutation associated with peripheral neuropathy in a family with Charcot–Marie–Tooth disease type 1E.MethodsTwo siblings previously reported to have genomic rearrangements predicted to involve exon 4 of PMP22 were evaluated clinically and by electrophysiology. Skin biopsies from the proband were studied by RT‐PCR to determine the effects of the exon 4 rearrangements on exon 4 mRNA expression in myelinating Schwann cells. Transient transfection studies with wild‐type and mutant PMP22 were performed in Cos7 and RT4 cells to determine the fate of the resultant mutant protein.ResultsBoth affected siblings had a sensorimotor dysmyelinating neuropathy with severely slow nerve conduction velocities (<10 m/sec). RT‐PCR studies of Schwann cell RNA from one of the siblings demonstrated a complete in‐frame deletion of PMP22 exon 4 (PMP22Δ4). Transfection studies demonstrated that PMP22Δ4 protein is retained within the endoplasmic reticulum and not transported to the plasma membrane.ConclusionsOur results confirm that that FoSTeS‐mediated genomic rearrangement produced a deletion of exon 4 of PMP22, resulting in expression of both PMP22 mRNA and protein lacking this sequence. In addition, we provide experimental evidence for endoplasmic reticulum retention of the mutant protein suggesting a gain‐of‐function mutational mechanism consistent with the observed CMT1E in this family. PMP22Δ4 is another example of a mutated myelin protein that is misfolded and contributes to the pathogenesis of the neuropathy.

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A frame shift mutation in the PMP22 gene in hereditary neuropathy with liability to pressure palsies

Cited by 202 publications

References 23 publications

Estimation of the Mutation Frequencies in Charcot-Marie-Tooth Disease Type 1 and Hereditary Neuropathy with Liability to Pressure Palsies: A European Collaborative Study

Estimation of the Mutation Frequencies in Charcot-Marie-Tooth Disease Type 1 and Hereditary Neuropathy with Liability to Pressure Palsies: A European Collaborative Study

Apoptotic phenotype induced by overexpression of wild-type gas3/PMP22: its relation to the demyelinating peripheral neuropathy CMT1A.

PMP22 exon 4 deletion causes ER retention of PMP22 and a gain‐of‐function allele in CMT1E

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