Advanced search
1 file | 410.32 KB Add to list

Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies

Author
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 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.
Keywords
CONGENITAL MYASTHENIC SYNDROMES, AFFINITY CHOLINE TRANSPORTER, NEUROMUSCULAR-JUNCTION, LOCALIZATION

Downloads

  • 2018Salter.pdf
    • full text
    • |
    • open access
    • |
    • PDF
    • |
    • 410.32 KB

Citation

Please use this url to cite or link to this publication:

MLA
Salter, Claire G., et al. “Truncating SLC5A7 Mutations Underlie a Spectrum of Dominant Hereditary Motor Neuropathies.” NEUROLOGY-GENETICS, vol. 4, no. 2, 2018, doi:10.1212/NXG.0000000000000222.
APA
Salter, C. G., Beijer, D., Hardy, H., Barwick, K. E., Bower, M., Mademan, I., … Crosby, A. H. (2018). Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies. NEUROLOGY-GENETICS, 4(2). https://doi.org/10.1212/NXG.0000000000000222
Chicago author-date
Salter, Claire G, Danique Beijer, Holly Hardy, Katy ES Barwick, Matthew Bower, Ines Mademan, Peter De Jonghe, et al. 2018. “Truncating SLC5A7 Mutations Underlie a Spectrum of Dominant Hereditary Motor Neuropathies.” NEUROLOGY-GENETICS 4 (2). https://doi.org/10.1212/NXG.0000000000000222.
Chicago author-date (all authors)
Salter, Claire G, Danique Beijer, Holly Hardy, Katy ES Barwick, Matthew Bower, Ines Mademan, Peter De Jonghe, Tine Deconinck, Mark A Russell, Meriel M McEntagart, Barry A Chioza, Randy D Blakely, John K Chilton, Jan De Bleecker, Jonathan Baets, Emma L Baple, David Walk, and Andrew H Crosby. 2018. “Truncating SLC5A7 Mutations Underlie a Spectrum of Dominant Hereditary Motor Neuropathies.” NEUROLOGY-GENETICS 4 (2). doi:10.1212/NXG.0000000000000222.
Vancouver
1.
Salter CG, Beijer D, Hardy H, Barwick KE, Bower M, Mademan I, et al. Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies. NEUROLOGY-GENETICS. 2018;4(2).
IEEE
[1]
C. G. Salter et al., “Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies,” NEUROLOGY-GENETICS, vol. 4, no. 2, 2018.
@article{8618379,
  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 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.},
  articleno    = {e222},
  author       = {Salter, Claire G and Beijer, Danique and Hardy, Holly and Barwick, Katy ES and Bower, Matthew and Mademan, Ines and De Jonghe, Peter and Deconinck, Tine and Russell, Mark A and McEntagart, Meriel M and Chioza, Barry A and Blakely, Randy D and Chilton, John K and De Bleecker, Jan and Baets, Jonathan and Baple, Emma L and Walk, David and Crosby, Andrew H},
  issn         = {2376-7839},
  journal      = {NEUROLOGY-GENETICS},
  keywords     = {CONGENITAL MYASTHENIC SYNDROMES,AFFINITY CHOLINE TRANSPORTER,NEUROMUSCULAR-JUNCTION,LOCALIZATION},
  language     = {eng},
  number       = {2},
  pages        = {8},
  title        = {Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies},
  url          = {http://dx.doi.org/10.1212/NXG.0000000000000222},
  volume       = {4},
  year         = {2018},
}

Altmetric
View in Altmetric
Web of Science
Times cited: