Myelin protein zero Val102fs mutation manifesting with isolated spinal root hypertrophy

Marchini, C.; Marsala, Sandro Zambito; Bendini, Matteo; Taioli, Federica; Damante, Giuseppe; Lonigro, Incoronata Renata; Fabrizi, Gian Maria

doi:10.1016/j.nmd.2009.09.004

Cited by 9 publications

(10 citation statements)

References 14 publications

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“…Moreover, it has been shown that Ser63del MPZ acts as a dominant negative that also results in wild‐type MPZ retention in the ER24; as such reducing S63del translation may permit more wild‐type MPZ to be released to reach the myelin membrane. Fifty percent of normal MPZ is known to be adequate for normal myelin formation as haploinsufficiency of MPZ does not cause a clinical neuropathy in patients 25, 26. Whether less than 50% of normal MPZ will also permit compact myelin formation is not yet known.…”

Section: Discussionmentioning

confidence: 99%

Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B

Bai

Brennan

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo determine the prevalence of MPZ mutations that cause Charcot Marie Tooth neuropathy type 1B (CMT1B) and activate the unfolded protein Response (UPR).Background CMT1B is caused by >200 heterozygous mutations in MPZ, the major protein in peripheral nerve myelin. Mutations Ser63del MPZ and Arg98Cys MPZ cause the mutant protein to be retained in the ER and activate the generally adaptive UPR. Treatments that modulate UPR activation have improved cellular and rodent models of CMT1B raising the possibility that other MPZ mutations that activate the UPR would also respond favorably to similar treatment. The prevalence of MPZ mutations that activate the UPR is unknown.MethodsWe developed a dual luciferase reporter assay of Xbp1 splicing using stably transfected RT4 Schwann cells to assay the ability of cDNA constructs bearing 46 distinct MPZ mutations to activate the UPR. Constructs also carried an HA tag to permit detection of ER retention of mutant proteins. UPR activation and ER retention were correlated with clinical phenotypes.ResultsEighteen mutations demonstrated ER retention and UPR activation to a similar degree as Ser63del and Arg98Cys MPZ. Thirty‐five of the mutations activated the UPR > 1.5 fold compared to that of wild‐type MPZ. Correlation was high between firefly and Nano‐luciferase reporters and between both reporters and ER localization. UPR activity did not correlate with clinical onset or severity.ConclusionMany CMT1B causing mutations activate the UPR and may be susceptible to therapeutic efforts to facilitate UPR function.

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Section: Discussionmentioning

confidence: 99%

Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B

Bai

Brennan

et al. 2018

Ann Clin Transl Neurol

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“…Conversely the phenotype of the present case appears to be milder (CMTNS 9 at age 41), with somewhat later symptom onset. Phenotype variability for identical mutations has been already described in other forms of CMT [8,9].…”

Section: Discussionmentioning

confidence: 65%

Clinical, electrophysiological and pathological findings of a patient with CMT2 due to the p.Ala738Val mitofusin 2 mutation

Luigetti

Fabrizi

Taioli

et al. 2011

Journal of the Neurological Sciences

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“…; Marchini et al. ) (Table , Appendix S1). Also in our cohort, three CMT1B patients with a MPZ mutation presented a hypertrophic cauda equina.…”

Section: Discussionmentioning

confidence: 99%

Underestimated associated features in CMT neuropathies: clinical indicators for the causative gene?

et al. 2016

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IntroductionCharcot–Marie–Tooth neuropathy (CMT) is a genetically heterogeneous group of peripheral neuropathies. In addition to the classical clinical phenotype, additional features can occur.MethodsWe studied a wide range of additional features in a cohort of 49 genetically confirmed CMT patients and performed a systematic literature revision.ResultsPatients harbored a PMP22 gene alteration (n = 28) or a mutation in MPZ (n = 11), GJB1 (n = 4), LITAF (n = 2), MFN2 (n = 2), INF2 (n = 1), NEFL (n = 1). We identified four novel mutations (3 MPZ, 1 GJB1). A total of 88% presented at least one additional feature. In MPZ patients, we detected hypertrophic nerve roots in 3/4 cases that underwent spinal MRI, and pupillary abnormalities in 27%. In our cohort, restless legs syndrome (RLS) was present in 18%. We describe for the first time RLS associated with LITAF or MFN2 and predominant upper limb involvement with LITAF. Cold‐induced hand cramps occurred in 10% (PMP22,MPZ,MFN2), and autonomous nervous system involvement in 18% (PMP22,MPZ, LITAF,MFN2). RLS and respiratory insufficiency were mostly associated with severe neuropathy, and pupillary abnormalities with mild to moderate neuropathy.ConclusionsIn CMT patients, additional features occur frequently. Some of them might be helpful in orienting genetic diagnosis. Our data broaden the clinical spectrum and genotype–phenotype associations with CMT.

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Myelin protein zero Val102fs mutation manifesting with isolated spinal root hypertrophy

Cited by 9 publications

References 14 publications

Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B

Myelin protein zero mutations and the unfolded protein response in Charcot Marie Tooth disease type 1B

Clinical, electrophysiological and pathological findings of a patient with CMT2 due to the p.Ala738Val mitofusin 2 mutation

Underestimated associated features in CMT neuropathies: clinical indicators for the causative gene?

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