X-linked Charcot-Marie-Tooth disease

Mostacciuolo, Maria Luisa; Müller, Elvira; Fardin, P; Micaglio, G. F.; Bardoni, Barbara; Guioli, Silvana; Camerino, Giovanna; Danieli, Gian Antonio

doi:10.1007/bf01213086

Cited by 32 publications

(5 citation statements)

References 14 publications

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“…The population carrier frequency (0.68 %; allele frequency, 0.34 %) is below that usually observed for a polymorphism and in accordance with autosomal recessive inheritance (Table 1). The incidence of 1:88,000 (Hardy–Weinberg, q 2 = 1.1391 −5 ) is concordant with other recessive types of CMT [2]. We analyzed 2,064 chromosomes of Central American, European, and US American ancestry and found seven heterozygous p.A335V carriers; five were healthy controls from Costa Rica (632 Costa Rican controls analyzed), one was a healthy control from Germany (23 German controls analyzed), and one was a female CMT1 patient with unknown genetic defect from Germany (377 patients analyzed).…”

Section: Resultssupporting

confidence: 57%

Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models

et al. 2009

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Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous disorder. All mendelian patterns of inheritance have been described. We identified a homozygous p.A335V mutation in the MED25 gene in an extended Costa Rican family with autosomal recessively inherited Charcot-Marie-Tooth neuropathy linked to the CMT2B2 locus in chromosome 19q13.3. MED25, also known as ARC92 and ACID1, is a subunit of the human activator-recruited cofactor (ARC), a family of large transcriptional coactivator complexes related to the yeast Mediator. MED25 was identified by virtue of functional association with the activator domains of multiple cellular and viral transcriptional activators. Its exact physiological function in transcriptional regulation remains obscure. The CMT2B2-associated missense amino acid substitution p.A335V is located in a proline-rich region with high affinity for SH3 domains of the Abelson type. The mutation causes a decrease in binding specificity leading to the recognition of a broader range of SH3 domain proteins. Furthermore, Med25 is coordinately expressed with Pmp22 gene dosage and expression in transgenic mice and rats. These results suggest a potential role of this protein in the molecular etiology of CMT2B2 and suggest a potential, more general role of MED25 in gene dosage sensitive peripheral neuropathy pathogenesis.

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Section: Resultssupporting

confidence: 57%

Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models

et al. 2009

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“…Additional heterogeneity was shown by genetic linkage with markers of the Xq13.1 region, thus identifying an X‐linked dominant variant form (CMTX). 13–21 Such families demonstrated the distinctive clinical criteria of an X‐linked mode of inheritance, showing an absence of male‐to‐male transmission and a more severe disease phenotype in affected males compared to that in affected females of the same age. 22–26 Linkage studies and recombination analysis mapped CMTX to the proximal long arm of the X chromosome at Xq13.1, a region that also contained the gene locus of the connexin32 (Cx32) gap junction protein.…”

Section: Introductionmentioning

confidence: 99%

Genotype/Phenotype Correlations in X‐Linked Dominant Charcot‐Marie‐Tooth Disease

Hahn

Bolton

White

et al. 1999

Annals of the New York Academy of Sciences

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We have studied the relationship between genotype, clinical phenotype, and pathology in 13 families with dominant X-linked Charcot-Marie-Tooth (CMT) neuropathy. Connexin32 (Cx32) gene mutations were spread throughout the coding region and included eight missense mutations, one 8-bp deletion/4-bp insertion frame shifting mutation, two nonsense mutations, and one deletion of the entire coding sequence. One hundred sixteen affected CMTX patients (53 males and 63 females) and 63 unaffected, at-risk individuals were compared by neurological and electrophysiological examinations and analyzed by gender; nerve biopsies were available from seven index cases. It was found that mutations within all regions of the Cx32 gene coding sequence caused an identical clinical phenotype. Male CMTX patients were affected more severely and showed an age-dependent progression of clinical signs and of the pathology; there was, however, variability in the severity of disease expression, irrespective of age, among males within families of defined genotype. All but 10% of female CMTX patients had only mild signs. Motor nerve conduction velocities were moderately slowed (median nerve MNCV: males 34.5 +/- 6.2 m/sec; females 45.8 +/- 7.3 m/sec), and motor and sensory nerve amplitudes were reduced (median nerve CMAP: males 3.7 +/- 3.7 mV; females 7.8 +/- 3.4 mV), with electromyographic evidence of chronic denervation. Differences were significant between gender and between affected and unaffected individuals. In agreement with the electrophysiological observations, pathological studies showed evidence of paranodal demyelination and of a length-related axonal degeneration in motor and sensory nerve fibers. Correlations between genotype and clinical phenotype suggested that missense mutations located within the second transmembrane domain and/or cytoplasmic loop might be associated with milder clinical phenotype, and therefore might be less disruptive of connexin32 gap junction function. Missense, chain-terminating, or deletion mutations in all other locations of the connexin32 protein caused severe forms of CMTX and disease onset in the first decade. Observed variability of disease severity among males within kinships suggests the influence of other modifying factors.

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“…Such potential altering of the availability of MED25 may affect transcriptional activation or regulation of target genes in the peripheral nervous system. We further document that Pmp22 expression correlates with Med25 expression levels in: (1) transgenic animals, both mice and rats, wherein the Pmp22 expression is altered by effectively changing gene copy number, (2) in animals wherein the Pmp22 expression is altered by epigenetic means, and (3) in a nerve-crush/injury paradigm. These latter findings suggest that PMP22 may be at least one of the genes downstream of MED25 that is mediating the neuropathic effects of the p.A335V mutation.…”

Section: Discussionmentioning

confidence: 71%

“…is concordant with other recessive types of CMT [2]. We analyzed 2,064 chromosomes of Central American, European, and US American ancestry and found seven heterozygous p.A335V carriers; five were healthy controls from Costa Rica (632 Costa Rican controls analyzed), one was a healthy control from Germany (23 German controls analyzed), and one was a female CMT1 patient with unknown genetic defect from Germany (377 patients analyzed).…”

Section: Identification Of the Neuropathy Causing Homozygous Med25 Mumentioning

confidence: 92%

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Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models

et al. 2009

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X-linked Charcot-Marie-Tooth disease

Cited by 32 publications

References 14 publications

Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models

Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models

Genotype/Phenotype Correlations in X‐Linked Dominant Charcot‐Marie‐Tooth Disease

Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models

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