Two novel connexin32 mutations cause early onset X-linked Charcot-Marie-Tooth disease

Braathen, Geir J.; Sand, Jette C; Bukholm, Geir; Russell, Michael Bjørn

doi:10.1186/1471-2377-7-19

Cited by 5 publications

(3 citation statements)

References 37 publications

(43 reference statements)

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“…Interestingly, all of these genes encode proteins with functions in endocytosis and membrane trafficking, suggesting that defects in these cellular processes may contribute to the pathogenesis of CMT disease. Finally, mutations in GJB1 (gap junction protein β 1; also known as connexin 32 [83,84]) also result in CMT disease [85,86]. …”

Section: Mtms/mtmrs In Diseasementioning

confidence: 99%

The myotubularin family of lipid phosphatases in disease and in spermatogenesis

Mruk

Cheng

2010

Biochemical Journal

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The MTM (myotubularin)/MTMR (myotubularin-related) protein family is comprised of 15 lipid phosphatases, of which nine members are catalytically active. MTMs are known to play a fundamental role in human physiology as gene mutations can give rise to X-linked myotubular myopathy or Charcot–Marie–Tooth disease, which manifest in skeletal muscle or in peripheral neurons respectively. Interestingly, studies have shown MTMR2 and MTMR5, two MTM family members, to be highly expressed in the testis, particularly in Sertoli and germ cells, and knockout of either gene resulted in spermatogenic defects. Other studies have shown that MTMR2 functions in endocytosis and membrane trafficking. In the testis, MTMR2 interacts and co-localizes with c-Src/phospho-Src-(Tyr416), a non-receptor protein tyrosine kinase that regulates the phosphorylation state of proteins at the apical ES (ectoplasmic specialization), a unique type of cell junction found between Sertoli cells and elongating/elongated spermatids. In the present review, we highlight recent findings that have made a significant impact on our understanding of this protein family in normal cell function and in disease, with the emphasis on the role of MTMs and MTMRs in spermatogenesis. We also describe a working model to explain how MTMR2 interacts with other proteins such as c-Src, dynamin 2, EPS8 (growth factor receptor pathway substrate 8) and ARP2/3 (actin-related protein 2/3) at the apical ES and the apical TBC (tubulobulbar complex; tubular-like invaginations that function in the disassembly of the apical ES and in the recycling of its components) to regulate spermiation at late stage VIII of the seminiferous epithelial cycle.

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Section: Mtms/mtmrs In Diseasementioning

confidence: 99%

The myotubularin family of lipid phosphatases in disease and in spermatogenesis

Mruk

Cheng

2010

Biochemical Journal

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“…Epidemiological studies suggest a prevalence from 1.6 to 41 per 100,000 inhabitants, according to different areas under study, adopted diagnostic criteria and patient recruitment modality [7] . In the world, there are few CMT epidemiological studies.…”

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confidence: 99%

Epidemiology of Charcot-Marie-Tooth Disease in the Population of Belgrade, Serbia

Mladenović

Rašić²,

Marković³

et al. 2011

Neuroepidemiology

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Background: The aim of this study was to determine prevalence and 15-year survival in Charcot-Marie-Tooth disease (CMT). Methods: The study covers the period from 1 January 1988 to 31 December 2007 in the territory of Belgrade. Data on a number of CMT-affected persons and their basic demographic characteristics as well as data on the disease were collected from medical records. Data on the course and outcome of the disease were obtained through direct contact with patients, their families and their physicians. Results: We registered 161 patients with CMT in the population of Belgrade. The most frequent type was CMT1. The crude prevalence of CMT disease in the Belgrade population on 31 December 2007 was 9.7/100,000 for all subtypes, 7.1/100,000 for CMT1, and 2.3/100,000 for CMT2. Gender-specific prevalence was 11.2/100,000 for males and 8.3/100,000 for females. The highest age-specific prevalence was registered in the oldest age group (75+ years; 19.1/100,000), and the lowest one in patients aged 5–14 years (5.0/100,000). The cumulative probability of 15-year survival for CMT patients in Belgrade was 85.6 ± 7.8% (44.9 ± 31.8% for males and 98.2 ± 1.8% for females). Conclusions: The prevalence of CMT found in Belgrade is similar to the prevalence registered in Southern European countries.

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“…Heterozygous females are usually latently affected and have a milder phenotype. Median or ulnar motor nerve conduction velocities (MNCVs) are typically 30–40 m/sec in affected males and 30–50 m/sec in affected females . To date, more than 400 GJB1 mutations have been reported (http://www.molgen.ua.ac.be/CMTMutations/), indicating that almost all of the residues are required for the normal functioning of gap junction (GJ) beta‐1 protein (GJB1) …”

Section: Introductionmentioning

confidence: 99%

Clinical and biophysical characterization of 19 GJB1 mutations

Tsai

Yang

Liao

et al. 2016

Ann Clin Transl Neurol

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ObjectiveCharcot–Marie–Tooth disease type X1 (CMTX1), which is caused by mutations in the gap junction (GJ) protein beta‐1 gene (GJB1), is the second most common form of Charcot–Marie–Tooth disease (CMT). GJB1 encodes the GJ beta‐1 protein (GJB1), which forms GJs within the myelin sheaths of peripheral nerves. The process by which GJB1 mutants cause neuropathy has not been fully elucidated. This study evaluated the biophysical characteristics of GJB1 mutants and their correlations with the clinical features of CMTX1 patients.MethodsAll patients with a validated GJB1 mutation were assessed using the Charcot–Marie–Tooth disease neuropathy score version 2 (CMTNS). The impacts of the mutations on the biophysical functions of GJB1 were characterized by assessing intracellular localization, expression patterns, and GJ Ca2+ permeability.ResultNineteen GJB1 mutations were identified in 24 patients with a clinical diagnosis of CMT. Six are novel mutations: p.L6S, p.I20F, p.I101Rfs*8, p.F153L, p.R215P, and p.D278V. Diverse pathological effects of the mutations were demonstrated, including reduced GJB1 expression, intracellular mislocalization, and altered GJ functions. GJB1 mutations that caused a complete loss of GJ Ca2+ permeability appeared to be associated with an earlier disease onset, whereas those resulting in preservation of GJ permeability and with predominant cell membrane expression tended to have a later onset and a milder phenotype.InterpretationThis study demonstrated that the degree of loss of GJ function caused by the GJB1 mutations might contribute to the onset and severity of neuropathic symptoms in CMTX1.

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Two novel connexin32 mutations cause early onset X-linked Charcot-Marie-Tooth disease

Abstract: Background: X-linked Charcot-Marie Tooth (CMT) is caused by mutations in the connexin32 gene that encodes a polypeptide which is arranged in hexameric array and form gap junctions.

Cited by 5 publications

References 37 publications

The myotubularin family of lipid phosphatases in disease and in spermatogenesis

The myotubularin family of lipid phosphatases in disease and in spermatogenesis

Epidemiology of Charcot-Marie-Tooth Disease in the Population of Belgrade, Serbia

Clinical and biophysical characterization of 19 GJB1 mutations

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