Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans.
OBJECTIVE
To identify the genetic cause of a syndrome causing cerebellar ataxia and eye movement abnormalities.


METHODS
We identified 2 families with cerebellar ataxia, eye movement abnormalities, and global developmental delay. We performed genetic analyses including single nucleotide polymorphism genotyping, linkage analysis, array comparative genomic hybridization, quantitative PCR, and Sanger sequencing. We obtained eye movement recordings of mutant mice deficient for the ortholog of the identified candidate gene, and performed immunohistochemistry using human and mouse brain specimens.


RESULTS
All affected individuals had ataxia, eye movement abnormalities, most notably tonic upgaze, and delayed speech and cognitive development. Homozygosity mapping identified the disease locus on chromosome 4q. Within this region, a homozygous deletion of GRID2 exon 4 in the index family and compound heterozygous deletions involving GRID2 exon 2 in the second family were identified. Grid2-deficient mice showed larger spontaneous and random eye movements compared to wild-type mice. In developing mouse and human cerebella, GRID2 localized to the Purkinje cell dendritic spines. Brain MRI in 2 affected children showed progressive cerebellar atrophy, which was more severe than that of Grid2-deficient mice.


CONCLUSIONS
Biallelic deletions of GRID2 lead to a syndrome of cerebellar ataxia and tonic upgaze in humans. The phenotypic resemblance and similarity in protein expression pattern between humans and mice suggest a conserved role for GRID2 in the synapse organization between parallel fibers and Purkinje cells. However, the progressive and severe cerebellar atrophy seen in the affected individuals could indicate an evolutionarily unique role for GRID2 in the human cerebellum.
From the Division of Genetics (L.B.H., A.-T.N.L., R.S.H., J.N.P., M.A.-S., J.M.S., G.H.M.) and Division of Developmental Medicine (R.N.), Department of Medicine, and Howard Hughes Medical Institute (J.N.P.), Boston Children's Hospital, Boston, MA; Division of Child Neurology (A.M.), Department of Pediatrics, Jordan University Hospital, Amman, Jordan; Department of Anatomy (K.K., M.W.), Hokkaido University Graduate School of Medicine, Sapporo, Japan; Department of Physiology (W.K., M.Y.), School of Medicine, Keio University, Tokyo, Japan; Department of Pediatrics (E.L.-M., N.C.), New York Medical College, Valhalla, NY; Department of Pediatrics (M.A.-S.), Faculty of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates; Department of Pediatrics (R.N., J.M.S., G.H.M.), Harvard Medical School, Boston, MA; Department of Radiology and Biomedical Imaging (A.J.B.), University of California, San Francisco; and Pediatric Neurology Unit (G.H.M.), Department of Neurology, Massachusetts General Hospital, Boston.
L Benjamin
LB
Hills
Amira
A
Masri
Kotaro
K
Konno
Wataru
W
Kakegawa
Anh-Thu N
AT
Lam
Elizabeth
E
Lim-Melia
Nandini
N
Chandy
R Sean
RS
Hill
Jennifer N
JN
Partlow
Muna
M
Al-Saffar
Ramzi
R
Nasir
Joan M
JM
Stoler
A James
AJ
Barkovich
Masahiko
M
Watanabe
Michisuke
M
Yuzaki
Ganeshwaran H
GH
Mochida
D000293:Adolescent; D000818:Animals; D002524:Cerebellar Ataxia / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D005260:Female; D005808:Genes, Recessive / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D015835:Ocular Motility Disorders / Q000235:genetics*; D017470:Receptors, Glutamate / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics; D013577:Syndrome
D017470:Receptors, Glutamate; C107913:glutamate receptor delta 2