Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies.
dc.contributor.author | Salter, CG | |
dc.contributor.author | Beijer, D | |
dc.contributor.author | Hardy, H | |
dc.contributor.author | Barwick, KES | |
dc.contributor.author | Bower, M | |
dc.contributor.author | Mademan, I | |
dc.contributor.author | De Jonghe, P | |
dc.contributor.author | Deconinck, T | |
dc.contributor.author | Russell, MA | |
dc.contributor.author | McEntagart, MM | |
dc.contributor.author | Chioza, BA | |
dc.contributor.author | Blakely, RD | |
dc.contributor.author | Chilton, JK | |
dc.contributor.author | De Bleecker, J | |
dc.contributor.author | Baets, J | |
dc.contributor.author | Baple, EL | |
dc.contributor.author | Walk, D | |
dc.contributor.author | Crosby, AH | |
dc.date.accessioned | 2018-04-19T09:31:28Z | |
dc.date.issued | 2018-03-03 | |
dc.description.abstract | Objective: To identify the genetic cause of disease in 2 previously unreported families with forms of distal hereditary motor neuropathies (dHMNs). Methods: The first family comprises individuals affected by dHMN type V, which lacks the cardinal clinical feature of vocal cord paralysis characteristic of dHMN-VII observed in the second family. Next-generation sequencing was performed on the proband of each family. Variants were annotated and filtered, initially focusing on genes associated with neuropathy. Candidate variants were further investigated and confirmed by dideoxy sequence analysis and cosegregation studies. Thorough patient phenotyping was completed, comprising clinical history, examination, and neurologic investigation. Results: dHMNs are a heterogeneous group of peripheral motor neuron disorders characterized by length-dependent neuropathy and progressive distal limb muscle weakness and wasting. We previously reported a dominant-negative frameshift mutation located in the concluding exon of theSLC5A7gene encoding the choline transporter (CHT), leading to protein truncation, as the likely cause of dominantly-inherited dHMN-VII in an extended UK family. In this study, our genetic studies identified distinct heterozygous frameshift mutations located in the last coding exon ofSLC5A7, predicted to result in the truncation of the CHT C-terminus, as the likely cause of the condition in each family. Conclusions: This study corroborates C-terminal CHT truncation as a cause of autosomal dominant dHMN, confirming upper limb predominating over lower limb involvement, and broadening the clinical spectrum arising from CHT malfunction. | en_GB |
dc.description.sponsorship | This work was supported by the Association Belge contre les Maladies Neuromusculaire (ABMM)—Aide à la Recherche ASBL and the EU FP7/2007 2013 under grant agreement number 2012—305121 (NEUROMICS), the Medical Research Council (G1002279 to A.H.C.), and the Neurosciences Research Foundation (to A.H.C. and E.L.B.). J.B. is supported by a Senior Clinical Researcher mandate of the Research Fund—Flanders (FWO). | en_GB |
dc.identifier.citation | Vol. 4 (2), article e222 | en_GB |
dc.identifier.doi | 10.1212/NXG.0000000000000222 | |
dc.identifier.uri | http://hdl.handle.net/10871/32506 | |
dc.language.iso | en | en_GB |
dc.publisher | Lippincott, Williams & Wilkins | en_GB |
dc.relation.source | Data access: the research materials supporting this publication can be accessed by contacting the corresponding author. | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/29582019 | en_GB |
dc.rights | This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. | en_GB |
dc.title | Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies. | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2018-04-19T09:31:28Z | |
dc.identifier.issn | 2376-7839 | |
exeter.place-of-publication | United States | en_GB |
dc.description | This is the final version of the article. Available from Lippincott, Williams & Wilkins via the DOI in this record. | en_GB |
dc.identifier.journal | Neurology Genetics | en_GB |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ |
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