title: Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion.
abstract: OBJECTIVE
  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.Gly30_Glu81del) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Kristof
authors.initials: K
authors.lastname: Van Schil
authors.affiliation: Department of Pediatric Ophthalmology, Queen Fabiola Children's University Hospital, Brussels, Belgium.
authors.forename: Françoise
authors.initials: F
authors.lastname: Meire
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Karlstetter
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Miriam
authors.initials: M
authors.lastname: Bauwens
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Hannah
authors.initials: H
authors.lastname: Verdin
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Frauke
authors.initials: F
authors.lastname: Coppieters
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Scheiffert
authors.affiliation: Unite Troubles de l'Equilibré et Vertiges, CHU Brugmann, Brussels, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Van Nechel
authors.affiliation: Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Langmann
authors.affiliation: Department of Pediatric Neurology, Queen Fabiola Children's University Hospital, Brussels, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Deconinck
authors.affiliation: Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Elfride
authors.initials: E
authors.lastname: De Baere
mesh_terms: D000818:Animals; D002675:Child, Preschool; D056915:DNA Copy Number Variations / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D051379:Mice; D010375:Pedigree; D017470:Receptors, Glutamate / Q000096:biosynthesis / Q000235:genetics*; D012160:Retina / Q000378:metabolism / Q000473:pathology; D058499:Retinal Dystrophies / Q000150:complications / Q000235:genetics* / Q000473:pathology; D017384:Sequence Deletion; D013132:Spinocerebellar Degenerations / Q000150:complications / Q000235:genetics* / Q000473:pathology
chemical_list: D017470:Receptors, Glutamate; C107913:glutamate receptor delta 2