Novel <i>PLEKHG5</i> mutations in a patient with childhood‐onset lower motor neuron disease

Gonzalez‐Quereda, Lidia; Pagola, Inmaculada; Fuentes‐Prior, Pablo; Bernal, Sara; Rodrí­guez, Marí­a José; Torné, Laura; Salgado-Garrido, Josefa; Gallano, P.; Jericó, Ivonne

doi:10.1002/acn3.51265

Cited by 5 publications

(3 citation statements)

References 16 publications

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“…Despite the different clinical phenotypes reported so far, no genotype-phenotype correlations have been identified to date. Truncating as well as missense variants affecting both main functional domains, inter-domains, N-terminal or C-terminal parts of the protein, were associated with either CMT [4,5] or LMND (HMN, DSMA4 or SMA) [3,7,8,38]. The site of the mutation and the potential involvement of the functional protein domains or the predicted impact of the mutation have not been associated with the phenotype variability among reported families.…”

Section: Discussionmentioning

confidence: 91%

“…So far, fifteen families carrying biallelic PLEKHG5 pathogenic variants have been reported [3][4][5][6][7][8]. Patients presented with either LMND (or DSMA4), in the first family reported [3] and in more recently reported patients [6,7], or with a proximal and distal motor neuropathy with initial prominent proximal weakness and mild sensory involvement in 3 families [6], or with an intermediate CMT phenotype exhibiting significant clinical and neurophysiological sensory involvement in six families [4][5][6].…”

Section: Discussionmentioning

confidence: 99%

“…More recently, cases with either pure lower motor neuron disease (LMND), distal and proximal neuropathy with mild sensory involvement or intermediate-CM have been documented [6][7][8]. Here, we report two additional families carrying novel PLEKHG5 mutations presenting with an intermediate CMT phenotype associated with atypical findings, including leukoencephalopathy, conduction blocks on electrophysiological studies and highly elevated creatine kinase (CK), thus expanding the phenotypical spectrum of the disease.…”

Section: Introductionmentioning

confidence: 93%

See 2 more Smart Citations

Leukoencephalopathy and conduction blocks in PLEKHG5-associated intermediate CMT disease

Villar-Quiles¹,

Le²,

Léonard-Louis³

et al. 2021

Neuromuscular Disorders

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

See 1 more Smart Citation

Leukoencephalopathy and conduction blocks in PLEKHG5-associated intermediate CMT disease

Villar-Quiles¹,

Le²,

Léonard-Louis³

et al. 2021

Neuromuscular Disorders

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Plekhg5 controls the unconventional secretion of Sod1 by presynaptic secretory autophagy

Hutchings,

Hambrecht,

Veh

et al. 2024

Nat Commun

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Increasing evidence suggests an essential function for autophagy in unconventional protein secretion (UPS). However, despite its relevance for the secretion of aggregate-prone proteins, the mechanisms of secretory autophagy in neurons have remained elusive. Here we show that the lower motoneuron disease-associated guanine exchange factor Plekhg5 drives the UPS of Sod1. Mechanistically, Sod1 is sequestered into autophagosomal carriers, which subsequently fuse with secretory lysosomal-related organelles (LROs). Exocytosis of LROs to release Sod1 into the extracellular milieu requires the activation of the small GTPase Rab26 by Plekhg5. Deletion of Plekhg5 in mice leads to the accumulation of Sod1 in LROs at swollen presynaptic sites. A reduced secretion of toxic ALS-linked SOD1G93A following deletion of Plekhg5 in SOD1G93A mice accelerated disease onset while prolonging survival due to an attenuated microglia activation. Using human iPSC-derived motoneurons we show that reduced levels of PLEKHG5 cause an impaired secretion of ALS-linked SOD1. Our findings highlight an unexpected pathophysiological mechanism that converges two motoneuron disease-associated proteins into a common pathway.

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The RhoGEF protein Plekhg5 self-associates via its PH domain to regulate apical cell constriction

Popov,

Tao,

Chang

2024

MBoC

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RhoGEFs are critical activators of Rho family small GTPases and regulate diverse biological processes, such as cell division and tissue morphogenesis. We reported previously that the RhoGEF gene plekhg5 controls apical constriction of bottle cells at the blastopore lip during Xenopus gastrulation, but the detailed mechanism of plekhg5 action is not understood in depth. In this study, we show that localization of Plekhg5 in the apical cortex depends on its N-terminal sequences and intact guanine nucleotide exchange activity, whereas the C-terminal sequences prevent ectopic localization of the protein to the basolateral compartment. We also reveal that Plekhg5 self-associates via its PH domain, and this interaction leads to functional rescue of two mutants that lack the N-terminal region and the GEF activity, respectively, in trans. A point mutation in the PH domain corresponding to a variant associated with human disease leads to loss of self-association and failure of the mutant to induce apical constriction. Taken together, our results suggest that PH-mediated self-association and N-terminal domain-mediated subcellular localization are both crucial for the function of Plekhg5 in inducing apical constriction. [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text] [Media: see text]

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Novel PLEKHG5 mutations in a patient with childhood‐onset lower motor neuron disease

Cited by 5 publications

References 16 publications

Leukoencephalopathy and conduction blocks in PLEKHG5-associated intermediate CMT disease

Leukoencephalopathy and conduction blocks in PLEKHG5-associated intermediate CMT disease

Plekhg5 controls the unconventional secretion of Sod1 by presynaptic secretory autophagy

The RhoGEF protein Plekhg5 self-associates via its PH domain to regulate apical cell constriction

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