Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans

L. Benjamin Hills, Amira Masri, Kotaro Konno, Wataru Kakegawa, Anh Thu N Lam, Elizabeth Lim-Melia, Nandini Chandy, R. Sean Hill, Jennifer N. Partlow, Muna Al-Saffar, Ramzi Nasir, Joan M. Stoler, A. James Barkovich, Masahiko Watanabe, Michisuke Yuzaki, Ganeshwaran H. Mochida

Research output: Contribution to journalArticle

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Abstract

Objective: To identify the genetic cause of a syndrome causing cerebellar ataxia and eye movement abnormalities. Methods: Weidentified 2 families with cerebellar ataxia, eyemovement 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.

Original languageEnglish
Pages (from-to)1378-1386
Number of pages9
JournalNeurology
Volume81
Issue number16
DOIs
Publication statusPublished - 2013 Oct 15

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Cerebellar Ataxia
Eye Movements
Eye Abnormalities
Purkinje Cells
Cerebellum
Atrophy
Exons
Dendritic Spines
Comparative Genomic Hybridization
Brain
Ataxia
Mouse
Syndrome
Tonic
Synapses
Single Nucleotide Polymorphism
Chromosomes
Immunohistochemistry
Polymerase Chain Reaction
Genes

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Hills, L. B., Masri, A., Konno, K., Kakegawa, W., Lam, A. T. N., Lim-Melia, E., ... Mochida, G. H. (2013). Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans. Neurology, 81(16), 1378-1386. https://doi.org/10.1212/WNL.0b013e3182a841a3

Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans. / Hills, L. Benjamin; Masri, Amira; Konno, Kotaro; Kakegawa, Wataru; Lam, Anh Thu N; Lim-Melia, Elizabeth; Chandy, Nandini; Hill, R. Sean; Partlow, Jennifer N.; Al-Saffar, Muna; Nasir, Ramzi; Stoler, Joan M.; Barkovich, A. James; Watanabe, Masahiko; Yuzaki, Michisuke; Mochida, Ganeshwaran H.

In: Neurology, Vol. 81, No. 16, 15.10.2013, p. 1378-1386.

Research output: Contribution to journalArticle

Hills, LB, Masri, A, Konno, K, Kakegawa, W, Lam, ATN, Lim-Melia, E, Chandy, N, Hill, RS, Partlow, JN, Al-Saffar, M, Nasir, R, Stoler, JM, Barkovich, AJ, Watanabe, M, Yuzaki, M & Mochida, GH 2013, 'Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans', Neurology, vol. 81, no. 16, pp. 1378-1386. https://doi.org/10.1212/WNL.0b013e3182a841a3
Hills, L. Benjamin ; Masri, Amira ; Konno, Kotaro ; Kakegawa, Wataru ; Lam, Anh Thu N ; Lim-Melia, Elizabeth ; Chandy, Nandini ; Hill, R. Sean ; Partlow, Jennifer N. ; Al-Saffar, Muna ; Nasir, Ramzi ; Stoler, Joan M. ; Barkovich, A. James ; Watanabe, Masahiko ; Yuzaki, Michisuke ; Mochida, Ganeshwaran H. / Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans. In: Neurology. 2013 ; Vol. 81, No. 16. pp. 1378-1386.
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abstract = "Objective: To identify the genetic cause of a syndrome causing cerebellar ataxia and eye movement abnormalities. Methods: Weidentified 2 families with cerebellar ataxia, eyemovement 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.",
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T1 - Deletions in GRID2 lead to a recessive syndrome of cerebellar ataxia and tonic upgaze in humans

AU - Hills, L. Benjamin

AU - Masri, Amira

AU - Konno, Kotaro

AU - Kakegawa, Wataru

AU - Lam, Anh Thu N

AU - Lim-Melia, Elizabeth

AU - Chandy, Nandini

AU - Hill, R. Sean

AU - Partlow, Jennifer N.

AU - Al-Saffar, Muna

AU - Nasir, Ramzi

AU - Stoler, Joan M.

AU - Barkovich, A. James

AU - Watanabe, Masahiko

AU - Yuzaki, Michisuke

AU - Mochida, Ganeshwaran H.

PY - 2013/10/15

Y1 - 2013/10/15

N2 - Objective: To identify the genetic cause of a syndrome causing cerebellar ataxia and eye movement abnormalities. Methods: Weidentified 2 families with cerebellar ataxia, eyemovement 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.

AB - Objective: To identify the genetic cause of a syndrome causing cerebellar ataxia and eye movement abnormalities. Methods: Weidentified 2 families with cerebellar ataxia, eyemovement 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.

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