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Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion

Kristof Van Schil UGent, Françoise Meire, Marcus Karlstetter, Miriam Bauwens UGent, Hannah Verdin UGent, Frauke Coppieters, Eva Scheiffert, Christian Van Nechel, Thomas Langmann, Nicolas Deconinck, et al. (2015) GENETICS IN MEDICINE. 17(4). p.291-299
abstract
Purpose: The aim of this study was to identify the genetic cause of early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy in a consanguineous family. Methods: An affected 6-month-old child underwent neurological and ophthalmological examinations. Genetic analyses included homozygosity mapping, copy number analysis, conventional polymerase chain reaction, Sanger sequencing, quantitative polymerase chain reaction, and whole-exome sequencing. Expression analysis of GRID2 was performed by quantitative polymerase chain reaction and immunohistochemistry. Results: A homozygous deletion of exon 2 of GRID2 (p.G1y30_Glu-81del) was identified in the proband. GRID2 encodes an ionotropic glutamate receptor known to be selectively expressed in cerebellar Purkinje cells. Here, we demonstrated GRID2 expression in human adult retina and retinal pigment epithelium. In addition, Grid2 expression was demonstrated in different stages of murine retinal development. GRID2 immunostaining was shown in murine and human retina. Whole-exome sequencing in the proband did not provide arguments for other disease-causing mutations, supporting the idea that the phenotype observed represents a single clinical entity. Conclusion: We identified GRID2 as an underlying disease gene of early-onset autosomal recessive cerebellar ataxia with retinal dystrophy, expanding the clinical spectrum of GRID2 deletion mutants. We demonstrated for the first time GRID2 expression and localization in human and murine retina, providing evidence for a novel functional role of GRID2 in the retina.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
glutamate receptor, autosomal recessive cerebellar ataxia, GRID2, hotfoot, retinal dystrophy, DELTA-2 GLUTAMATE-RECEPTOR, TIME QUANTITATIVE PCR, PURKINJE-CELLS, HOT-SPOT, MUTATIONS, GENE, SUBUNIT, GLUTAMATE-RECEPTOR-DELTA-2, EXPRESSION
journal title
GENETICS IN MEDICINE
Genet. Med.
volume
17
issue
4
pages
291 - 299
Web of Science type
Article
Web of Science id
000352466900007
JCR category
GENETICS & HEREDITY
JCR impact factor
7.71 (2015)
JCR rank
13/165 (2015)
JCR quartile
1 (2015)
ISSN
1098-3600
DOI
10.1038/gim.2014.95
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
5846920
handle
http://hdl.handle.net/1854/LU-5846920
date created
2015-02-12 13:57:54
date last changed
2016-12-19 15:42:01
@article{5846920,
  abstract     = {Purpose: The aim of this study was to identify the genetic cause of early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy in a consanguineous family. 
Methods: An affected 6-month-old child underwent neurological and ophthalmological examinations. Genetic analyses included homozygosity mapping, copy number analysis, conventional polymerase chain reaction, Sanger sequencing, quantitative polymerase chain reaction, and whole-exome sequencing. Expression analysis of GRID2 was performed by quantitative polymerase chain reaction and immunohistochemistry. 
Results: A homozygous deletion of exon 2 of GRID2 (p.G1y30\_Glu-81del) was identified in the proband. GRID2 encodes an ionotropic glutamate receptor known to be selectively expressed in cerebellar Purkinje cells. Here, we demonstrated GRID2 expression in human adult retina and retinal pigment epithelium. In addition, Grid2 expression was demonstrated in different stages of murine retinal development. GRID2 immunostaining was shown in murine and human retina. Whole-exome sequencing in the proband did not provide arguments for other disease-causing mutations, supporting the idea that the phenotype observed represents a single clinical entity. 
Conclusion: We identified GRID2 as an underlying disease gene of early-onset autosomal recessive cerebellar ataxia with retinal dystrophy, expanding the clinical spectrum of GRID2 deletion mutants. We demonstrated for the first time GRID2 expression and localization in human and murine retina, providing evidence for a novel functional role of GRID2 in the retina.},
  author       = {Van Schil, Kristof and Meire, Fran\c{c}oise and Karlstetter, Marcus and Bauwens, Miriam and Verdin, Hannah and Coppieters, Frauke and Scheiffert, Eva and Van Nechel, Christian and Langmann, Thomas and Deconinck, Nicolas and De Baere, Elfride},
  issn         = {1098-3600},
  journal      = {GENETICS IN MEDICINE},
  keyword      = {glutamate receptor,autosomal recessive cerebellar ataxia,GRID2,hotfoot,retinal dystrophy,DELTA-2 GLUTAMATE-RECEPTOR,TIME QUANTITATIVE PCR,PURKINJE-CELLS,HOT-SPOT,MUTATIONS,GENE,SUBUNIT,GLUTAMATE-RECEPTOR-DELTA-2,EXPRESSION},
  language     = {eng},
  number       = {4},
  pages        = {291--299},
  title        = {Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion},
  url          = {http://dx.doi.org/10.1038/gim.2014.95},
  volume       = {17},
  year         = {2015},
}

Chicago
Van Schil, Kristof, Françoise Meire, Marcus Karlstetter, Miriam Bauwens, Hannah Verdin, Frauke Coppieters, Eva Scheiffert, et al. 2015. “Early-onset Autosomal Recessive Cerebellar Ataxia Associated with Retinal Dystrophy: New Human Hotfoot Phenotype Caused by Homozygous GRID2 Deletion.” Genetics in Medicine 17 (4): 291–299.
APA
Van Schil, K., Meire, F., Karlstetter, M., Bauwens, M., Verdin, H., Coppieters, F., Scheiffert, E., et al. (2015). Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion. GENETICS IN MEDICINE, 17(4), 291–299.
Vancouver
1.
Van Schil K, Meire F, Karlstetter M, Bauwens M, Verdin H, Coppieters F, et al. Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion. GENETICS IN MEDICINE. 2015;17(4):291–9.
MLA
Van Schil, Kristof, Françoise Meire, Marcus Karlstetter, et al. “Early-onset Autosomal Recessive Cerebellar Ataxia Associated with Retinal Dystrophy: New Human Hotfoot Phenotype Caused by Homozygous GRID2 Deletion.” GENETICS IN MEDICINE 17.4 (2015): 291–299. Print.