Skin biopsies demonstrate MPZ splicing abnormalities in Charcot-Marie-Tooth neuropathy 1B

Sabet, Arman; Li, J.; Ghandour, Khaled; Qin, Pu; Wu, Xiaohua; Kamholz, John; Shy, Michael E.; Cambi, Franca

doi:10.1212/01.wnl.0000238499.37764.b1

Cited by 39 publications

(27 citation statements)

References 18 publications

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“…[12][13][14][15][16][17][18][19] Decreased ENFs/mm has also been shown to be characteristic of generalized sensorimotor neuropathies of various kinds. 7,13,15,[20][21][22][23][24][25][26][27] Consensus panels have accepted the assessment of ENFs as objective and valid indications of small sensory nerve fiber involvement in disease.…”

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confidence: 99%

Epidermal nerve fibers

et al. 2012

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Objectives: Our first objective was to explore the value of estimating 95% confidence intervals (CIs) of epidermal nerve fibers (ENFs)/mm for number of sections to be evaluated and for confidently judging normality or abnormality. Our second objective was to introduce a new continuous measure combining nerve conduction and ENFs/mm. Methods:The 95% CI studies were performed on 1, 1-2, 1-3 ---1-10 serial skip sections of 3-mm punch biopsies of leg and thigh of 67 healthy subjects and 23 patients with diabetes mellitus.Results: Variability of differences of ENFs/mm counts (and 95% CIs) from evaluation of 1, 1-2, 1-3 ---1-9 compared with 1-10 serial skip sections decreased progressively without a break point with increasing numbers of sections evaluated. Estimating 95% CIs as sections are evaluated can be used to judge how many sections are needed for adequate evaluation, i.e., only a few when counts and 95% CIs are well within the range of normality or abnormality and more when values are borderline. Also provided is a methodology to combine results of nerve conduction and ENFs/mm as continuous measures of normality or abnormality.Conclusion: Estimating 95% CIs of ENFs/mm is useful to judge how many sections should be evaluated to confidently declare counts to be normal or abnormal. Also introduced is a continuous measure of both large-fiber (nerve conduction) and small-fiber (ENFs/mm) normal structures/functions spanning the range of normality and abnormality for use in therapeutic trials. Neurology Enumeration of nerve endings in skin has been used to study differences among species, 1,2 development, maturation and aging, 3,4 and disease. 5,6 Light microscopic analysis of immune-stained intraepidermal nerve fibers (ENFs) and reference values were introduced to serve as objective and spatial indications of painful and small-fiber sensory polyneuropathy, "possibly useful for therapeutic trials." [7][8][9] The technique of biopsy was found to be acceptable to patients, and the estimation of ENFs/mm had high intraobserver and interobserver reproducibility.8 A somewhat different approach using punch skin biopsy, a blister technique with immunofluorescence and confocal microscopy, was also described (reviewed in Kennedy and Wendelschafer-Crabb 10 and Kennedy et al. 11). A series of reports showed the value of ENFs/mm in the diagnosis of painful small-fiber sensory polyneuropathy, especially in patients with few or no neurologic signs or test abnormalities.

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Epidermal nerve fibers

et al. 2012

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“…Among the more than 100 mutations of the MPZ gene leading to CMT, only three of them are splice-site mutations (http://www.molgen.ua.ac.be/CMTMutations/) [13][14][15][16][17]. The mutation has been described by Seeman et al [18]; however, this mutation is not found in an article, and personal communication revealed that the mutation has not yet been clinically and genetically described that way.…”

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confidence: 99%

Four novel mutations of the myelin protein zero gene presenting as a mild and late-onset polyneuropathy

et al. 2010

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Inherited neuropathies caused by mutations of the major structural protein of peripheral myelin, myelin protein zero (MPZ), contribute to 5% of all cases of Charcot-Marie-Tooth disease (CMT). They can be divided into an early-onset neuropathy with symptoms prior to the stage of walking, and a late-onset neuropathy with symptoms at the age of 40 and older. In this study, five patients with four novel MPZ mutations were identified by molecular genetic testing which presented as mild and late-onset neuropathies. We recommend testing for MPZ mutations in patients with a late-onset neuropathy, as late-onset inherited neuropathies might be more frequent than previously thought.

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“…The skin sample was evaluated as described previously 15. The sample was treated in freshly prepared RNALater (Qiagen, CA, Cat.…”

Section: Methodsmentioning

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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Skin biopsies demonstrate MPZ splicing abnormalities in Charcot-Marie-Tooth neuropathy 1B

Abstract: Intronic mutations cause CMT1B by disrupting splicing and certain MPZ mutations may cause neuropathy by interacting with the wild type MPZ in the extracellular space of compact myelin.

Cited by 39 publications

References 18 publications

Epidermal nerve fibers

Epidermal nerve fibers

Four novel mutations of the myelin protein zero gene presenting as a mild and late-onset polyneuropathy

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

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