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Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies

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 characteristi...

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Autores principales: Salter, Claire G., Beijer, Danique, Hardy, Holly, Barwick, Katy E.S., Bower, Matthew, Mademan, Ines, De Jonghe, Peter, Deconinck, Tine, Russell, Mark A., McEntagart, Meriel M., Chioza, Barry A., Blakely, Randy D., Chilton, John K., De Bleecker, Jan, Baets, Jonathan, Baple, Emma L., Walk, David, Crosby, Andrew H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wolters Kluwer 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866402/
https://www.ncbi.nlm.nih.gov/pubmed/29582019
http://dx.doi.org/10.1212/NXG.0000000000000222
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author Salter, Claire G.
Beijer, Danique
Hardy, Holly
Barwick, Katy E.S.
Bower, Matthew
Mademan, Ines
De Jonghe, Peter
Deconinck, Tine
Russell, Mark A.
McEntagart, Meriel M.
Chioza, Barry A.
Blakely, Randy D.
Chilton, John K.
De Bleecker, Jan
Baets, Jonathan
Baple, Emma L.
Walk, David
Crosby, Andrew H.
author_facet Salter, Claire G.
Beijer, Danique
Hardy, Holly
Barwick, Katy E.S.
Bower, Matthew
Mademan, Ines
De Jonghe, Peter
Deconinck, Tine
Russell, Mark A.
McEntagart, Meriel M.
Chioza, Barry A.
Blakely, Randy D.
Chilton, John K.
De Bleecker, Jan
Baets, Jonathan
Baple, Emma L.
Walk, David
Crosby, Andrew H.
author_sort Salter, Claire G.
collection PubMed
description 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 the SLC5A7 gene 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 of SLC5A7, 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.
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spelling pubmed-58664022018-03-26 Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies Salter, Claire G. Beijer, Danique Hardy, Holly Barwick, Katy E.S. Bower, Matthew Mademan, Ines De Jonghe, Peter Deconinck, Tine Russell, Mark A. McEntagart, Meriel M. Chioza, Barry A. Blakely, Randy D. Chilton, John K. De Bleecker, Jan Baets, Jonathan Baple, Emma L. Walk, David Crosby, Andrew H. Neurol Genet Article 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 the SLC5A7 gene 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 of SLC5A7, 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. Wolters Kluwer 2018-03-23 /pmc/articles/PMC5866402/ /pubmed/29582019 http://dx.doi.org/10.1212/NXG.0000000000000222 Text en Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Article
Salter, Claire G.
Beijer, Danique
Hardy, Holly
Barwick, Katy E.S.
Bower, Matthew
Mademan, Ines
De Jonghe, Peter
Deconinck, Tine
Russell, Mark A.
McEntagart, Meriel M.
Chioza, Barry A.
Blakely, Randy D.
Chilton, John K.
De Bleecker, Jan
Baets, Jonathan
Baple, Emma L.
Walk, David
Crosby, Andrew H.
Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies
title Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies
title_full Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies
title_fullStr Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies
title_full_unstemmed Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies
title_short Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies
title_sort truncating slc5a7 mutations underlie a spectrum of dominant hereditary motor neuropathies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866402/
https://www.ncbi.nlm.nih.gov/pubmed/29582019
http://dx.doi.org/10.1212/NXG.0000000000000222
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