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DTx Pharma Study Discovers Multiple Therapeutic Candidates for CMT1A

July 1, 2020

DTx Pharma Study Discovers Multiple Therapeutic Candidates for CMT1A

DTx Pharma Study Discovers Multiple Therapeutic Candidates for CMT1A

De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy

August 22, 2019

https://jmg.bmj.com/content/early/2019/08/22/jmedgenet-2019-106273

https://www.ncbi.nlm.nih.gov/pubmed/31439721?dopt=Abstract

De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy.

J Med Genet. 2019 Aug 22;:

Authors: Park J, Flores BR, Scherer K, Kuepper H, Rossi M, Rupprich K, Rautenberg M, Deininger N, Weichselbaum A, Grimm A, Sturm M, Grasshoff U, Delpire E, Haack TB

Abstract

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in SLC12A6 have been associated with autosomal-recessive hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). We identified heterozygous de novo variants in SLC12A6 in three unrelated patients with intermediate CMT.

METHODS: We evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in SLC12A6 identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in Xenopus oocytes.

RESULTS: We identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in SLC12A6 in three unrelated individuals with early-onset progressive CMT. All presented with axonal/demyelinating sensorimotor neuropathy accompanied by spasticity in one patient. Cognition and brain MRI were normal. Modelling of the mutant KCC3 cotransporter in Xenopus oocytes showed a significant reduction in potassium influx for both changes.

CONCLUSION: Our findings expand the genotypic and phenotypic spectrum associated with SLC12A6 variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy.

PMID: 31439721 [PubMed – as supplied by publisher]

PubMed:31439721

Park J, Flores BR, Scherer K, Kuepper H, Rossi M, Rupprich K, Rautenberg M, Deininger N, Weichselbaum A, Grimm A, Sturm M, Grasshoff U, Delpire E, Haack TB

ATP1A1 mutations cause intermediate Charcot-Marie-Tooth disease

August 2, 2019

https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.23886

https://www.ncbi.nlm.nih.gov/pubmed/31373411?dopt=Abstract

ATP1A1 mutations cause intermediate Charcot-Marie-Tooth disease.

Hum Mutat. 2019 Aug 02;:

Authors: He J, Guo L, Lin S, Chen W, Xu G, Cai B, Xu L, Hong J, Qiu L, Wang N, Chen W

Abstract

Intermediate Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of inherited neuropathies characterized by progressive muscle weakness and atrophy of the distal extremities, distal sensory loss. There were still a large proportion of causative genes for intermediate CMT failed to be identified. Here, using whole-exome sequencing technique, we identified two novel missense mutations in ATP1A1 gene, c.620C>T (p.S207F) and c.2629G>A (p.G877S), in two Chinese CMT families. Further functional analysis revealed that these mutations led to loss function of the ATP1A1 protein. The two mutations did not affect the levels of mRNA but possessed a damaging effect on ATP1A1 protein expression and they downregulated the protein levels of ATP1A1 by promoting its proteasome degradation. Taken together, we confirmed ATP1A1 as a novel causative gene for intermediate CMT. This article is protected by copyright. All rights reserved.

PMID: 31373411 [PubMed – as supplied by publisher]

PubMed:31373411

He J, Guo L, Lin S, Chen W, Xu G, Cai B, Xu L, Hong J, Qiu L, Wang N, Chen W