Mutations in the PLEKHG5 gene is relevant with autosomal recessive intermediate Charcot-Marie-Tooth disease

Kim, Hyeon Jin; Hong, Young Bin; Park, Jin Mo; Choi, Yongju; Kim, Ye Jin; Yoon, Bo Ram; Koo, Heasoo; Yoo, Jeong Hyun; Kim, Sang Beom; Park, Minhwa; Chung, Ki Wha; Choi, Byung Ok

doi:10.1186/1750-1172-8-104

Cited by 34 publications

(37 citation statements)

References 28 publications

(27 reference statements)

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“…There are phosphoinositide-binding domains in several proteins linked to CMT, including dynamin2 (ref. 17), KIF1Bb 18 , neurofilament (NEFL) 19 , Pleckstrin homology (PH) domain containing, family G member 5 (PLEKHG5) 20 and Frabin/ FGD 21,22 . Notably, mutations in the PI(4,5)P 2 -binding domains of dynamin2 (ref.…”

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confidence: 99%

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TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2

et al. 2014

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Mutations in the ankyrin repeat domain (ARD) of TRPV4 are responsible for several channelopathies, including Charcot-Marie-Tooth disease type 2C and congenital distal and scapuloperoneal spinal muscular atrophy. However, the molecular pathogenesis mediated by these mutations remains elusive, mainly due to limited understanding of the TRPV4 ARD function. Here we show that phosphoinositide binding to the TRPV4 ARD leads to suppression of the channel activity. Among the phosphoinositides, phosphatidylinositol-4,5-bisphosphate (PI(4,5)P 2 ) most potently binds to the TRPV4 ARD. The crystal structure of the TRPV4 ARD in complex with inositol-1,4,5-trisphosphate, the head-group of PI(4,5)P 2 , and the molecular-dynamics simulations revealed the PI(4,5)P 2 -binding amino-acid residues. The TRPV4 channel activities were increased by titration or hydrolysis of membrane PI(4,5)P 2 . Notably, disease-associated TRPV4 mutations that cause a gain-of-function phenotype abolished PI(4,5)P 2 binding and PI(4,5)P 2 sensitivity. These findings identify TRPV4 ARD as a lipid-binding domain in which interactions with PI(4,5)P 2 normalize the channel activity in TRPV4.

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confidence: 99%

“…17) and PLEKHG5 (ref. 20) have been identified as the causes of CMT. In addition, several different CMT subtypes occur due to mutations in phosphoinositidespecific phosphatases 12 , including MTMR2, MTMR13 and FIG4.…”

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confidence: 99%

TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2

et al. 2014

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“…A combined axonal and demyelinating phenotype with similar histopathological changes was also found in AD CMT due to GDAP1 mutation [44]. pathogenesis and animal model PLEKHG5 is expressed by both neuronal and glial cells [47,48]. In vitro assays using transfected cells suggested that the missense mutants show impaired ability to activate the NFKB signaling pathway [46,48] and form intracellular aggregates [46].…”

Section: Histopathologymentioning

confidence: 70%

“…pathogenesis and animal model PLEKHG5 is expressed by both neuronal and glial cells [47,48]. In vitro assays using transfected cells suggested that the missense mutants show impaired ability to activate the NFKB signaling pathway [46,48] and form intracellular aggregates [46]. PLEKHG5 knockout mice showed reduced NCVs [47].…”

Section: Histopathologymentioning

confidence: 99%

Dominant and recessive intermediate CMT (CMTDI and CMTRI)

Weis

Roos

Katona

et al. 2014

Peripheral Nerve Disorders

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In 1978, Davis and colleagues suggested a classification of dominantly inherited peroneal muscular atrophy cases based on upper limb motor nerve conduction velocity (NCV) measurements. Cases with NCVs of >25 m/s were assigned to the demyelinating (or hypertrophic) neuropathy group, patients with NCVs between 25 and 45 m/s comprised the intermediate group and cases with NCVs >45 m/s were assigned to the axonal (or neuronal) sensorimotor neuropathy group [1]. Two years later, Harding and Thomas [2] proposed a median nerve motor NCV of 38 m/s as a cut-off value to distinguish between HMSN I (<38 m/s) and HMSN II (>38 m/s).

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“…Immunohistochemical studies revealed that the patients expressed a low level of PLEKHG5 in the distal sural nerve and in vitro assays suggested that the PLEKHG5 mutants are defective in activating the NF-κB signaling pathway [79] . Norwegian CMT cases and confirmed that MFN2 gene mutation can also cause intermediate CMT [80] .…”

Section: Plekhg5 and The Ri-cmtc Phenotypementioning

confidence: 99%

Intermediate Charcot-Marie-Tooth disease

Liu

Zhang

2014

Neurosci. Bull.

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Charcot-Marie-Tooth (CMT) disease is a common neurogenetic disorder and its heterogeneity is a challenge for genetic diagnostics. The genetic diagnostic procedures for a CMT patient can be explored according to the electrophysiological criteria: very slow motor nerve conduction velocity (MNCV) (<15 m/s), slow MNCV (15-25 m/s), intermediate MNCV (25-45 m/s), and normal MNCV (>45 m/s). Based on the inheritance pattern, intermediate CMT can be divided into dominant (DI-CMT) and recessive types (RI-CMT). GJB1 is currently considered to be associated with X-linked DI-CMT, and MPZ, INF2, DNM2, YARS, GNB4, NEFL, and MFN2 are associated with autosomal DI-CMT. Moreover, GDAP1, KARS, and PLEKHG5 are associated with RI-CMT. Identifi cation of these genes is not only important for patients and families but also provides new information about pathogenesis. It is hoped that this review will lead to a better understanding of intermediate CMT and provide a detailed diagnostic procedure for intermediate CMT.

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Mutations in the PLEKHG5 gene is relevant with autosomal recessive intermediate Charcot-Marie-Tooth disease

Cited by 34 publications

References 28 publications

TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2

TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2

Dominant and recessive intermediate CMT (CMTDI and CMTRI)

Intermediate Charcot-Marie-Tooth disease

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