A novel
            <i>Frabin</i>
            (FGD4) nonsense mutation p.R275X associated with phenotypic variability in CMT4H

Houlden, Henry; Hammans, Simon; Katifi, Haider; Reilly, Mary M.

doi:10.1212/01.wnl.0000342463.35089.cc

Cited by 32 publications

(25 citation statements)

References 10 publications

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“…FGD4 encodes for the protein FGD1-related F-actin binding protein (Frabin) and previous studies have shown specific point mutations in FGD4 can cause the congenital peripheral neuropathy Charcot-Marie-Tooth disease (CMT4H) (21–24). The disease is characterized by a slow progressive demyelination of peripheral sensory and motor neurons accompanied by distal muscle weakness and atrophy, sensory loss, hyporeflexia and skeletal deformity (25).…”

Section: Discussionmentioning

confidence: 99%

A Genome-Wide Association Study Identifies Novel Loci for Paclitaxel-Induced Sensory Peripheral Neuropathy in CALGB 40101

Baldwin

Owzar

Zembutsu

et al. 2012

Clinical Cancer Research

196

251

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Purpose: Sensory peripheral neuropathy is a common and sometimes debilitating toxicity associated with paclitaxel therapy. This study aims to identify genetic risk factors for the development of this toxicity.Experimental Design: A prospective pharmacogenetic analysis of patients with primary breast cancer, randomized to the paclitaxel arm of CALGB 40101, was used to identify genetic predictors of the onset and severity of sensory peripheral neuropathy. A genome-wide association study in 855 subjects of European ancestry was conducted and findings were replicated in additional European (n ¼ 154) and African American (n ¼ 117) subjects.Results: A single nucleotide polymorphism in FGD4 was associated with the onset of sensory peripheral neuropathy in the discovery cohort [rs10771973; HR, 1.57; 95% confidence interval (CI), 1.30-1.91; P ¼ 2.6 Â 10 À6] and in a European (HR, 1.72; 95% CI, 1.06-2.80; P ¼ 0.013) and African American (HR, 1.93; 95% CI, 1.13-3.28; P ¼ 6.7 Â 10 À3 ) replication cohort. There is also evidence that markers in additional genes, including EPHA5 (rs7349683) and FZD3 (rs10771973), were associated with the onset or severity of paclitaxel-induced sensory peripheral neuropathy.Conclusions: A genome-wide association study has identified novel genetic markers of paclitaxelinduced sensory peripheral neuropathy, including a common polymorphism in FGD4, a congenital peripheral neuropathy gene. These findings suggest that genetic variation may contribute to variation in development of this toxicity. Validation of these findings may allow for the identification of patients at increased risk of peripheral neuropathy and inform the use of an alternative to paclitaxel and/or the clinical management of this toxicity.

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Section: Discussionmentioning

confidence: 99%

A Genome-Wide Association Study Identifies Novel Loci for Paclitaxel-Induced Sensory Peripheral Neuropathy in CALGB 40101

Baldwin

Owzar

Zembutsu

et al. 2012

Clinical Cancer Research

196

251

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“…Other conditions that display this mutation-specific expression of disease severity include the clinical phenotypes of Marfan syndrome (MFS) (fibrillin-1; FBN1 ) [106, 107], Townes-Brocks syndrome (TBS) (sal-like 1; SALL1 ) [100], growth hormone insensitivity syndrome (GHIS) (growth hormone receptor; GHR ) [108], Charcot Marie Tooth type 4H (CMT4H) (Frabin; FGD4 ) [109, 110], Tay-Sachs disease (hexosaminidase A; HEXA ) [111], retinoblastoma (retinoblastoma; RB1 ) [112], and ataxia-telangiectasia (ataxia-telangiaectasia mutated; ATM ) [113]. In addition to the examples given above, we have shown previously that NMD recognizes numerous mutations from a variety of genes that cause neuronal ceroid lipofuscinosis (NCL), a group of fatal neurodegenerative disorders, leading to variable gene expression and subsequent differences in protein function and clinical severity [114-116].…”

Section: Nonsense-mediated Decay and Genetic Diseasementioning

confidence: 99%

Nonsense-mediated decay in genetic disease: Friend or foe?

Miller¹,

Pearce²

2014

Mutation Research/Reviews in Mutation Research

170

166

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Eukaryotic cells utilize various RNA quality control mechanisms to ensure high fidelity of gene expression, thus protecting against the accumulation of nonfunctional RNA and the subsequent production of abnormal peptides. Messenger RNAs (mRNAs) are largely responsible for protein production, and mRNA quality control is particularly important for protecting the cell against the downstream effects of genetic mutations. Nonsense-mediated decay (NMD) is an evolutionarily conserved mRNA quality control system in all eukaryotes that degrades transcripts containing premature termination codons (PTCs). By degrading these aberrant transcripts, NMD acts to prevent the production of truncated proteins that could otherwise harm the cell through various insults, such as dominant negative effects or the ER stress response. Although NMD functions to protect the cell against the deleterious effects of aberrant mRNA, there is a growing body of evidence that mutation-, codon-, gene-, cell-, and tissue-specific differences in NMD efficiency can alter the underlying pathology of genetic disease. In addition, the protective role that NMD plays in genetic disease can undermine current therapeutic strategies aimed at increasing the production of full-length functional protein from genes harboring nonsense mutations. Here, we review the normal function of this RNA surveillance pathway and how it is regulated, provide current evidence for the role that it plays in modulating genetic disease phenotypes, and how NMD can be used as a therapeutic target.

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“…A number of mutations of the fgd4 (also called frabin) gene are found in peripheral demyelinating Charcot-Marie-Tooth (CMT) neuropathy type 4H (CMT4H), which causes myelin outfoldings and deformed scoliosis (Delague et al, 2007;Stendel et al, 2007;Fabrizi et al, 2009;Houlden et al, 2009). FGD4 is a Dbl family GEF specific for Cdc42.…”

Section: Gefs For Rho Gtpases and Peripheral Myelin Formationmentioning

confidence: 99%

The Atypical Guanine-Nucleotide Exchange Factor, Dock7, Negatively Regulates Schwann Cell Differentiation and Myelination

Yamauchi¹,

Miyamoto²,

Hamasaki³

et al. 2011

J. Neurosci.

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A novel Frabin (FGD4) nonsense mutation p.R275X associated with phenotypic variability in CMT4H

Abstract: Background: Charcot Marie Tooth (CMT) disease is a heterogeneous group of inherited peripheral

Cited by 32 publications

References 10 publications

A Genome-Wide Association Study Identifies Novel Loci for Paclitaxel-Induced Sensory Peripheral Neuropathy in CALGB 40101

A Genome-Wide Association Study Identifies Novel Loci for Paclitaxel-Induced Sensory Peripheral Neuropathy in CALGB 40101

Nonsense-mediated decay in genetic disease: Friend or foe?

The Atypical Guanine-Nucleotide Exchange Factor, Dock7, Negatively Regulates Schwann Cell Differentiation and Myelination

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