A Novel Mutation in <i>FGD4/FRABIN</i> Causes Charcot Marie Tooth Disease Type 4H in Patients from a Consanguineous Tunisian Family

Boubaker, Chokri; Hsairi-Guidara, I.; Castro, Christel; Ayadi, I.; Boyer, Anthony; Kerkeni, Emna; Courageot, Joël; Abid, Imen; Bernard, R.; Bonello‐Palot, Nathalie; Kamoun, Fatma; Cheikh, Hassen Ben; Lévy, Nicolas; Triki, Chahnez; Delague, Valérie

doi:10.1111/ahg.12017

Cited by 13 publications

(27 citation statements)

References 23 publications

(53 reference statements)

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“…Although the effects of CMT4H-linked Frabin mutations on ErbB receptor trafficking have not been examined, a number of disease-causing Frabin mutations were found in its phosphoinositide-recognition domains, namely, the two PH domains with binding specificity to PI(3,4,5)P 3 , PI(4,5)P 2 , and PI(3,4)P 2 and one FYVE domain with binding specificity to PI(3)P [72, 117–119]. As described earlier, these phosphoinositides play important roles in regulation of ErbB2/ErbB3 receptor trafficking and signaling (Figs.…”

Section: Impaired Phosphoinositide-mediated Regulation Of Erbb Receptmentioning

confidence: 99%

Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot-Marie-Tooth Disease

Lee

Chin

2016

Mol Neurobiol

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Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy with the majority of cases involving demyelination of peripheral nerves. The pathogenic mechanisms of demyelinating CMT remain unclear, and no effective therapy currently exists for this disease. The discovery that mutations in different genes can cause a similar phenotype of demyelinating peripheral neuropathy raises the possibility that there may be convergent mechanisms leading to demyelinating CMT pathogenesis. Increasing evidence indicates that ErbB receptor-mediated signaling plays a major role in the control of Schwann cell-axon communication and myelination in the peripheral nervous system. Recent studies reveal that several demyelinating CMT-linked proteins are novel regulators of endocytic trafficking and/or phosphoinositide metabolism that may affect ErbB receptor signaling. Emerging data have begun to suggest that dysregulation of ErbB receptor trafficking and signaling in Schwann cells may represent a common pathogenic mechanism in multiple subtypes of demyelinating CMT. In this review, we focus on the roles of ErbB receptor trafficking and signaling in regulation of peripheral nerve myelination and discuss the emerging evidence supporting the potential involvement of altered ErbB receptor trafficking and signaling in demyelinating CMT pathogenesis and the possibility of modulating these trafficking and signaling processes for treating demyelinating peripheral neuropathy.

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Section: Impaired Phosphoinositide-mediated Regulation Of Erbb Receptmentioning

confidence: 99%

Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot-Marie-Tooth Disease

Lee

Chin

2016

Mol Neurobiol

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“…CMT4H is an autosomal recessive demyelinating subtype of Charcot-Marie-Tooth disease, that we have first described in 2005 (De Sandre-Giovannoli, Delague et al 2005) and for which we and others have described FGD4 as the gene causing the disease (Delague, Jacquier et al 2007, Stendel, Roos et al 2007. One distinctive feature of CMT4H is the presence, in the nerves of patients, of recurrent loops of myelin, called outfoldings (De Sandre-Giovannoli, Delague et al 2005, Stendel, Roos et al 2007, Fabrizi, Taioli et al 2009, Arai, Hayashi et al 2013, Boubaker, Hsairi-Guidara et al 2013) These rare myelination abnormalities, have also been reported in other autosomal recessive demyelinating subtypes of Charcot-Marie-Tooth, i.e. CMT4B1 (MIM 601382), CMT4B2 (MIM 604563), and CMT4F…”

Section: Discussionmentioning

confidence: 99%

“…The diagnosis is established by the presence of biallelic pathogenic variants in FGD4. More than 30 mutations are described to date in FGD4, most of them resulting in a loss of the protein or a nonfunctional truncated protein (Delague, Jacquier et al 2007, Baudot, Esteve et al 2012, Boubaker, Hsairi-Guidara et al 2013. FGD4 encodes FRABIN, a Guanine Exchange Factor (GEF), carrying a Dbl Homology domain responsible for GDP/GTP exchange on the small RhoGTPases and more particularly Cdc42 and Rac1 (Umikawa, Obaishi et al 1999, Ono, Nakanishi et al 2000.…”

Section: Introductionmentioning

confidence: 99%

Imbalance of Neuregulin1-ErbB2/3 signaling underlies altered myelin homeostasis in models of Charcot-Marie-Tooth disease type 4H

El-Bazzal

Ghata

Estève

et al. 2022

Preprint

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Charcot Marie Tooth disease (CMT) is one of the most common inherited neurological disorders, affecting either axons from the motor and/or sensory neurons or Schwann cells (SC) of the peripheral nervous system, and caused by more than 100 genes. We previously identified mutations in FGD4, as responsible for CMT4H, an autosomal recessive demyelinating form of CMT. FGD4 encodes FRABIN a GDP/GTP nucleotide exchange factor (GEF), particularly for the small GTPase cdc42. Remarkably, nerves from patients with CMT4H display excessive redundant myelin called outfoldings that arise from focal hypermyelination, suggesting that FRABIN could play a role in the control of PNS myelination. To gain insights into the role of FGD4/FRABIN in SC myelination, we generated a knock-out mouse model, with conditional ablation of fgd4 in SC. We showed that the specific deletion of FRABIN in SCs leads to aberrant myelination in vitro, in dorsal root ganglion (DRG)/SCs cocultures as well in vivo, in distal sciatic nerves. We observed that those myelination defects are related to an upregulation of some interactors of the NRG1 type III/ErbB2/3 signaling pathway, which is known to ensure a proper level of myelination in the PNS. Based on a yeast two- hybrid screen, we identified SNX3 as a new partner of FRABIN, which is involved in the regulation of endocytic trafficking. Interestingly, we showed that loss of FRABIN impairs endocytic trafficking which may contribute to the defective NRG1 type III/ErbB2/3 signaling and myelination. Finally, we showed that the reestablishment of proper levels of the NRG1 type III/ErbB2/3 pathway using Niacin treatment reduces myelin outfoldings in nerves of CMT4H mice. Overall, our work reveals a new role of FRABIN in the regulation of NRG1 type III/ErbB2/3 NRG1signaling and myelination and opens future therapeutic strategies based on the modulation of NRG1 type III/ErbB2/3 NRG1to reduce CMT4H pathology and more generally others demyelinating CMT.

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“…So far, at least 22 CMT4H families with FGD4 gene mutations have been reported (4,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). According to a review of the previous CMT4H cases, it is clinically characterized by early onset and slow progression, and most cases started their symptoms before 5 years old, ranging from birth to 2 nd decade (4,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). The severity of distal muscle weakness, amyotrophy, and sensory involvement varies between affected individuals.…”

Section: Discussionmentioning

confidence: 99%

Sibling Cases of Charcot-Marie-Tooth Disease Type 4H with a Homozygous <i>FGD4</i> Mutation and Cauda Equina Thickening

et al. 2021

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Charcot-Marie-Tooth disease type 4H (CMT4H) is an autosomal recessive inherited demyelinating neuropathy caused by an FYVE, RhoGEF, and a PH domain-containing protein 4 (FGD4) gene mutation. CMT4H is characterized by an early onset, slow progression, scoliosis, distal muscle atrophy, and foot deformities. We herein present sibling cases of CMT4H with a homozygous mutation in the FGD4 gene. Both patients exhibited cauda equina thickening on magnetic resonance imaging, which had not been reported among the previous CMT4H cases. This is the first report of CMT4H with a homozygous FGD4 c.1730G>A (p.Arg577Gln) mutation showing mild progression and cauda equina thickening.

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A Novel Mutation in FGD4/FRABIN Causes Charcot Marie Tooth Disease Type 4H in Patients from a Consanguineous Tunisian Family

Cited by 13 publications

References 23 publications

Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot-Marie-Tooth Disease

Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot-Marie-Tooth Disease

Imbalance of Neuregulin1-ErbB2/3 signaling underlies altered myelin homeostasis in models of Charcot-Marie-Tooth disease type 4H

Sibling Cases of Charcot-Marie-Tooth Disease Type 4H with a Homozygous <i>FGD4</i> Mutation and Cauda Equina Thickening

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