G2Cdb::Human Disease report

Disease id
D00000184
Name
Huntington's disease
Nervous system disease
yes

Genes (3)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00000026 GRIN2A
glutamate receptor, ionotropic, N-methyl D-aspartate 2A
Y (17018562) Single nucleotide polymorphism (SNP) Y
G00000026 GRIN2A
glutamate receptor, ionotropic, N-methyl D-aspartate 2A
Y (15742215) Polymorphism (P) Y
G00000027 GRIN2B
glutamate receptor, ionotropic, N-methyl D-aspartate 2B
Y (15742215) Polymorphism (P) Y
G00001312 GRIK2
glutamate receptor, ionotropic, kainate 2
Y (9108071) Repeat polymorphism (RP) Y
G00001312 GRIK2
glutamate receptor, ionotropic, kainate 2
Y (10522893) Repeat polymorphism (RP) Y
G00001312 GRIK2
glutamate receptor, ionotropic, kainate 2
Y (12821179) Repeat polymorphism (RP) Y
G00001312 GRIK2
glutamate receptor, ionotropic, kainate 2
Y (14755452) Repeat polymorphism (RP) Y
G00001312 GRIK2
glutamate receptor, ionotropic, kainate 2
Y (16959037) Single nucleotide polymorphism (SNP) N
G00001312 GRIK2
glutamate receptor, ionotropic, kainate 2
Y (17018562) Repeat polymorphism (RP) N

References

  • Replication of twelve association studies for Huntington's disease residual age of onset in large Venezuelan kindreds.

    Andresen JM, Gayán J, Cherny SS, Brocklebank D, Alkorta-Aranburu G, Addis EA, US-Venezuela Collaborative Research Group, Cardon LR, Housman DE and Wexler NS

    Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. jma@mit.edu

    Background: The major determinant of age of onset in Huntington's disease is the length of the causative triplet CAG repeat. Significant variance remains, however, in residual age of onset even after repeat length is factored out. Many genetic polymorphisms have previously shown evidence of association with age of onset of Huntington's disease in several different populations.

    Objective: To replicate these genetic association tests in 443 affected people from a large set of kindreds from Venezuela.

    Methods: Previously tested polymorphisms were analysed in the HD gene itself (HD), the GluR6 kainate glutamate receptor (GRIK2), apolipoprotein E (APOE), the transcriptional coactivator CA150 (TCERG1), the ubiquitin carboxy-terminal hydrolase L1 (UCHL1), p53 (TP53), caspase-activated DNase (DFFB), and the NR2A and NR2B glutamate receptor subunits (GRIN2A, GRIN2B).

    Results: The GRIN2A single-nucleotide polymorphism explains a small but considerable amount of additional variance in residual age of onset in our sample. The TCERG1 microsatellite shows a trend towards association but does not reach statistical significance, perhaps because of the uninformative nature of the polymorphism caused by extreme allele frequencies. We did not replicate the genetic association of any of the other genes.

    Conclusions: GRIN2A and TCERG1 may show true association with residual age of onset for Huntington's disease. The most surprising negative result is for the GRIK2 (TAA)(n) polymorphism, which has previously shown association with age of onset in four independent populations with Huntington's disease. The lack of association in the Venezuelan kindreds may be due to the extremely low frequency of the key (TAA)(16) allele in this population.

    Journal of medical genetics 2007;44;1;44-50

  • Genetic analysis of the GRIK2 modifier effect in Huntington's disease.

    Zeng W, Gillis T, Hakky M, Djoussé L, Myers RH, MacDonald ME and Gusella JF

    Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA. wzeng@coh.org

    Background: In Huntington's disease (HD), age at neurological onset is inversely correlated with the length of the CAG trinucleotide repeat mutation, but can be modified by genetic factors beyond the HD gene. Association of a relatively infrequent 16 TAA allele of a trinucleotide repeat polymorphism in the GRIK2 3'UTR with earlier than expected age at neurological onset has been suggested to reflect linkage disequilibrium with a functional polymorphism in GRIK2 or an adjacent gene.

    Results: We have tested this hypothesis by sequencing all GRIK2 exons, the exon-flanking sequences and 3'UTR in several individuals who were crucial to demonstrating the modifier effect, as they showed much earlier age at neurological onset than would be expected from the length of their HD CAG mutation. Though ten known SNPs were detected, no sequence variants were found in coding or adjacent sequence that could explain the modifier effect by linkage disequilibrium with the 16 TAA allele. Haplotype analysis using microsatellites, known SNPs and new variants discovered in the 3'UTR argues against a common ancestral origin for the 16 TAA repeat alleles in these individuals.

    Conclusion: These data suggest that the modifier effect is actually due to the TAA repeat itself, possibly via a functional consequence on the GRIK2 mRNA.

    Funded by: NINDS NIH HHS: NS16367, P50 NS016367

    BMC neuroscience 2006;7;62

  • NR2A and NR2B receptor gene variations modify age at onset in Huntington disease.

    Arning L, Kraus PH, Valentin S, Saft C, Andrich J and Epplen JT

    Department of Human Genetics, Ruhr University Bochum, Universitätsstrasse 150, 44801 Bochum, Germany. larissa.arning@rub.de

    N -Methyl-d-aspartate (NMDA) receptor-mediated excitotoxicity has been proposed to play a role in the pathogenesis of Huntington disease (HD), an autosomal dominantly inherited disorder associated with defined expansions in a stretch of perfect CAG repeats in the 5' part of the IT15 gene. The number of CAG repeat units is highly predictive for the age at onset (AO) in HD. However, AO is only modestly correlated with repeat length when the HD expansion range is in the high 30s or low 40s. Therefore, we investigated whether the genes for the different subunits composing the multimeric complexes of NMDA receptors (GRIN glutamate receptor, ionotropic, N-methyl-d-aspartate) represent candidates for modulating the AO of HD. In the studied cohort of 167 HD patients, the repeat range from 41 to 45 CAG units accounted for 30.8% of the variance in AO; 12.3% additional variance could be attributed to GRIN2B genotype variation and 4.5% to GRIN2A genotype variation. We conclude that these two genes, coding for NR2B and NR2A subtypes mainly expressed in the striatum, may influence the variability in AO of HD. Neuroprotective strategies for HD patients and persons at risk should be reconsidered in the light of these findings.

    Neurogenetics 2005;6;1;25-8

  • The gender effect in juvenile Huntington disease patients of Italian origin.

    Cannella M, Gellera C, Maglione V, Giallonardo P, Cislaghi G, Muglia M, Quattrone A, Pierelli F, Di Donato S and Squitieri F

    Neurological Institute IRCCS Neuromed, Pozzilli (IS), Italy.

    We analyzed a population of juvenile Huntington disease (HD) subjects of Italian origin (n = 57). The main aim of this study was to analyze the gender effect of the affected parent on age at onset and clinical presentation of offspring with juvenile HD. We also analyzed molecular features of the disease, including CAG mutation length and GluR6 gene polymorphism, according to the affected parent's gender. The mutation length was longer in paternally than in maternally transmitted HD juvenile patients (P = 0.025), nevertheless a similar mean early onset in the two groups (P > 0.05). This data was even enforced by that obtained from the whole cohort of patients included in the databank (n = 600) where, in the presence of increased mean parent-child CAG repeat change in paternal vs. maternal meiotic transmissions (+7.3 vs. +0.7 CAG, P = 0.0002), the mean parent-child year-of-onset change was similar in the two groups (-10.4 and -7.0 years, P > 0.05). A lower TAA-triplet in GluR6 was associated with an earlier age at onset in juvenile patients (P = 0.031, R2 = 0.10). When we added the GluR6 effect on age at onset to the CAG expanded number effect (P = 0.0001, R2 = 0.68) by multiple regression approach, the coefficient of determination R2 increased to 0.81. This effect in addition to the expanded CAG repeat number, found in juvenile and not in adult patients, was slightly enforced by paternal compared to maternal transmissions (R2=0.82). Our findings suggest the occurrence of a weaker effect of the paternal mutation on juvenile age at onset in our population, possibly amplified by other genetic factors, such as the TAA-triplet length in the GluR6 gene.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2004;125B;1;92-8

  • Modulation of age at onset in Huntington's disease and spinocerebellar ataxia type 2 patients originated from eastern India.

    Chattopadhyay B, Ghosh S, Gangopadhyay PK, Das SK, Roy T, Sinha KK, Jha DK, Mukherjee SC, Chakraborty A, Singhal BS, Bhattacharya AK and Bhattacharyya NP

    Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, 1/AF Bidhan Nagar, Kolkata 700 064, India.

    To identify the genetic modifier(s) that might alter the age at onset in Huntington's disease (HD) we have analyzed variations in GluR6 kainate receptor (GluR6), CA150 gene, Delta2642 and polymorphic CCG repeat variation in huntingtin (htt) gene in 77 HD patients and normal individuals. In addition, variation in the RAI1 gene was analyzed in 30 spinocerebellar ataxia (SCA2) patients and normal individuals to show the possible influence on the age at onset. Multiple regression analysis indicated that variation in GluR6 and CCG repeat genotype might explain 6.2% and 3.1%, respectively, of the variability in the age at onset in HD. Similar analysis with SCA2 patients indicated that RAI1 might explain about 13% of the variability in the age at onset. Specific alleles in GluR6 and CA150 locus were only observed in HD patients.

    Neuroscience letters 2003;345;2;93-6

  • Evidence for the GluR6 gene associated with younger onset age of Huntington's disease.

    MacDonald ME, Vonsattel JP, Shrinidhi J, Couropmitree NN, Cupples LA, Bird ED, Gusella JF and Myers RH

    Molecular Neurogenetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, USA.

    Huntington's disease (HD) is attributed to a triplet CAG repeat mutation, and about half of the variation in onset age can be explained by the size of the repeat expansion. Recently, a TAA repeat polymorphism in close linkage to the kainate receptor, GluR6, was reported related to onset age in HD. We examined this polymorphism in 258 unrelated HD-affected persons (172 from a clinic sample and 86 from a postmortem series). This study confirms that the 155 allele is associated with younger onset age of HD and suggests that it is in linkage disequilibrium with a variant of the GluR6 gene or another gene in this region.

    Funded by: NINDS NIH HHS: NS31862, R0-1NS16367

    Neurology 1999;53;6;1330-2

  • Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease.

    Rubinsztein DC, Leggo J, Chiano M, Dodge A, Norbury G, Rosser E and Craufurd D

    East Anglian Medical Genetics Service Molecular Genetics Laboratory, Addenbrooke's NHS Trust, Cambridge, United Kingdom.

    Huntington disease (HD) is associated with abnormal expansions of a CAG repeat close to the 5' end of the IT15 gene. We have assembled a set of 293 HD subjects whose ages of onset were known and sized their HD CAG repeats. These repeats accounted for 69% of the variance of age of onset when we used the most parsimonious model, which relates the logarithm of age of onset to a function of CAG repeat number. Since other familial factors have been proposed to influence the age of onset of HD, we have examined a number of candidate loci. The CAG repeat number on normal chromosomes, the delta2642 polymorphism in the HD gene, and apolipoprotein E genotypes did not affect the age of onset of HD. Although mitochondrial energy production defects in HD have led to suggestions that variants in the mitochondrial genome may be associated with clinical variability in HD, this suggestion was not supported by our preliminary experiments that examined the DdeI mitochondrial restriction fragment length polymorphism at position 10,394. Excitotoxicity has been a favored mechanism to explain the cell death in HD, particularly since intrastriatal injection of excitatory amino acids in animals creates HD-like pathology. Accordingly, we investigated the GluR6 kainate receptor. Of the variance in the age of onset of HD that was not accounted for by the CAG repeats, 13% could be attributed to GluR6 genotype variation. These data implicate GluR6-mediated excitotoxicity in the pathogenesis of HD and highlight the potential importance of this process in other polyglutamine repeat expansion diseases.

    Proceedings of the National Academy of Sciences of the United States of America 1997;94;8;3872-6

Literature (7)

Pubmed - human_disease

  • The gender effect in juvenile Huntington disease patients of Italian origin.

    Cannella M, Gellera C, Maglione V, Giallonardo P, Cislaghi G, Muglia M, Quattrone A, Pierelli F, Di Donato S and Squitieri F

    Neurological Institute IRCCS Neuromed, Pozzilli (IS), Italy.

    We analyzed a population of juvenile Huntington disease (HD) subjects of Italian origin (n = 57). The main aim of this study was to analyze the gender effect of the affected parent on age at onset and clinical presentation of offspring with juvenile HD. We also analyzed molecular features of the disease, including CAG mutation length and GluR6 gene polymorphism, according to the affected parent's gender. The mutation length was longer in paternally than in maternally transmitted HD juvenile patients (P = 0.025), nevertheless a similar mean early onset in the two groups (P > 0.05). This data was even enforced by that obtained from the whole cohort of patients included in the databank (n = 600) where, in the presence of increased mean parent-child CAG repeat change in paternal vs. maternal meiotic transmissions (+7.3 vs. +0.7 CAG, P = 0.0002), the mean parent-child year-of-onset change was similar in the two groups (-10.4 and -7.0 years, P > 0.05). A lower TAA-triplet in GluR6 was associated with an earlier age at onset in juvenile patients (P = 0.031, R2 = 0.10). When we added the GluR6 effect on age at onset to the CAG expanded number effect (P = 0.0001, R2 = 0.68) by multiple regression approach, the coefficient of determination R2 increased to 0.81. This effect in addition to the expanded CAG repeat number, found in juvenile and not in adult patients, was slightly enforced by paternal compared to maternal transmissions (R2=0.82). Our findings suggest the occurrence of a weaker effect of the paternal mutation on juvenile age at onset in our population, possibly amplified by other genetic factors, such as the TAA-triplet length in the GluR6 gene.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2004;125B;1;92-8

  • Evidence for the GluR6 gene associated with younger onset age of Huntington's disease.

    MacDonald ME, Vonsattel JP, Shrinidhi J, Couropmitree NN, Cupples LA, Bird ED, Gusella JF and Myers RH

    Molecular Neurogenetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, USA.

    Huntington's disease (HD) is attributed to a triplet CAG repeat mutation, and about half of the variation in onset age can be explained by the size of the repeat expansion. Recently, a TAA repeat polymorphism in close linkage to the kainate receptor, GluR6, was reported related to onset age in HD. We examined this polymorphism in 258 unrelated HD-affected persons (172 from a clinic sample and 86 from a postmortem series). This study confirms that the 155 allele is associated with younger onset age of HD and suggests that it is in linkage disequilibrium with a variant of the GluR6 gene or another gene in this region.

    Funded by: NINDS NIH HHS: NS31862, R0-1NS16367

    Neurology 1999;53;6;1330-2

Pubmed - other

  • Replication of twelve association studies for Huntington's disease residual age of onset in large Venezuelan kindreds.

    Andresen JM, Gayán J, Cherny SS, Brocklebank D, Alkorta-Aranburu G, Addis EA, US-Venezuela Collaborative Research Group, Cardon LR, Housman DE and Wexler NS

    Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. jma@mit.edu

    Background: The major determinant of age of onset in Huntington's disease is the length of the causative triplet CAG repeat. Significant variance remains, however, in residual age of onset even after repeat length is factored out. Many genetic polymorphisms have previously shown evidence of association with age of onset of Huntington's disease in several different populations.

    Objective: To replicate these genetic association tests in 443 affected people from a large set of kindreds from Venezuela.

    Methods: Previously tested polymorphisms were analysed in the HD gene itself (HD), the GluR6 kainate glutamate receptor (GRIK2), apolipoprotein E (APOE), the transcriptional coactivator CA150 (TCERG1), the ubiquitin carboxy-terminal hydrolase L1 (UCHL1), p53 (TP53), caspase-activated DNase (DFFB), and the NR2A and NR2B glutamate receptor subunits (GRIN2A, GRIN2B).

    Results: The GRIN2A single-nucleotide polymorphism explains a small but considerable amount of additional variance in residual age of onset in our sample. The TCERG1 microsatellite shows a trend towards association but does not reach statistical significance, perhaps because of the uninformative nature of the polymorphism caused by extreme allele frequencies. We did not replicate the genetic association of any of the other genes.

    Conclusions: GRIN2A and TCERG1 may show true association with residual age of onset for Huntington's disease. The most surprising negative result is for the GRIK2 (TAA)(n) polymorphism, which has previously shown association with age of onset in four independent populations with Huntington's disease. The lack of association in the Venezuelan kindreds may be due to the extremely low frequency of the key (TAA)(16) allele in this population.

    Journal of medical genetics 2007;44;1;44-50

  • Genetic analysis of the GRIK2 modifier effect in Huntington's disease.

    Zeng W, Gillis T, Hakky M, Djoussé L, Myers RH, MacDonald ME and Gusella JF

    Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA. wzeng@coh.org

    Background: In Huntington's disease (HD), age at neurological onset is inversely correlated with the length of the CAG trinucleotide repeat mutation, but can be modified by genetic factors beyond the HD gene. Association of a relatively infrequent 16 TAA allele of a trinucleotide repeat polymorphism in the GRIK2 3'UTR with earlier than expected age at neurological onset has been suggested to reflect linkage disequilibrium with a functional polymorphism in GRIK2 or an adjacent gene.

    Results: We have tested this hypothesis by sequencing all GRIK2 exons, the exon-flanking sequences and 3'UTR in several individuals who were crucial to demonstrating the modifier effect, as they showed much earlier age at neurological onset than would be expected from the length of their HD CAG mutation. Though ten known SNPs were detected, no sequence variants were found in coding or adjacent sequence that could explain the modifier effect by linkage disequilibrium with the 16 TAA allele. Haplotype analysis using microsatellites, known SNPs and new variants discovered in the 3'UTR argues against a common ancestral origin for the 16 TAA repeat alleles in these individuals.

    Conclusion: These data suggest that the modifier effect is actually due to the TAA repeat itself, possibly via a functional consequence on the GRIK2 mRNA.

    Funded by: NINDS NIH HHS: NS16367, P50 NS016367

    BMC neuroscience 2006;7;62

  • NR2A and NR2B receptor gene variations modify age at onset in Huntington disease.

    Arning L, Kraus PH, Valentin S, Saft C, Andrich J and Epplen JT

    Department of Human Genetics, Ruhr University Bochum, Universitätsstrasse 150, 44801 Bochum, Germany. larissa.arning@rub.de

    N -Methyl-d-aspartate (NMDA) receptor-mediated excitotoxicity has been proposed to play a role in the pathogenesis of Huntington disease (HD), an autosomal dominantly inherited disorder associated with defined expansions in a stretch of perfect CAG repeats in the 5' part of the IT15 gene. The number of CAG repeat units is highly predictive for the age at onset (AO) in HD. However, AO is only modestly correlated with repeat length when the HD expansion range is in the high 30s or low 40s. Therefore, we investigated whether the genes for the different subunits composing the multimeric complexes of NMDA receptors (GRIN glutamate receptor, ionotropic, N-methyl-d-aspartate) represent candidates for modulating the AO of HD. In the studied cohort of 167 HD patients, the repeat range from 41 to 45 CAG units accounted for 30.8% of the variance in AO; 12.3% additional variance could be attributed to GRIN2B genotype variation and 4.5% to GRIN2A genotype variation. We conclude that these two genes, coding for NR2B and NR2A subtypes mainly expressed in the striatum, may influence the variability in AO of HD. Neuroprotective strategies for HD patients and persons at risk should be reconsidered in the light of these findings.

    Neurogenetics 2005;6;1;25-8

  • Modulation of age at onset in Huntington's disease and spinocerebellar ataxia type 2 patients originated from eastern India.

    Chattopadhyay B, Ghosh S, Gangopadhyay PK, Das SK, Roy T, Sinha KK, Jha DK, Mukherjee SC, Chakraborty A, Singhal BS, Bhattacharya AK and Bhattacharyya NP

    Crystallography and Molecular Biology Division, Saha Institute of Nuclear Physics, 1/AF Bidhan Nagar, Kolkata 700 064, India.

    To identify the genetic modifier(s) that might alter the age at onset in Huntington's disease (HD) we have analyzed variations in GluR6 kainate receptor (GluR6), CA150 gene, Delta2642 and polymorphic CCG repeat variation in huntingtin (htt) gene in 77 HD patients and normal individuals. In addition, variation in the RAI1 gene was analyzed in 30 spinocerebellar ataxia (SCA2) patients and normal individuals to show the possible influence on the age at onset. Multiple regression analysis indicated that variation in GluR6 and CCG repeat genotype might explain 6.2% and 3.1%, respectively, of the variability in the age at onset in HD. Similar analysis with SCA2 patients indicated that RAI1 might explain about 13% of the variability in the age at onset. Specific alleles in GluR6 and CA150 locus were only observed in HD patients.

    Neuroscience letters 2003;345;2;93-6

  • Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease.

    Rubinsztein DC, Leggo J, Chiano M, Dodge A, Norbury G, Rosser E and Craufurd D

    East Anglian Medical Genetics Service Molecular Genetics Laboratory, Addenbrooke's NHS Trust, Cambridge, United Kingdom.

    Huntington disease (HD) is associated with abnormal expansions of a CAG repeat close to the 5' end of the IT15 gene. We have assembled a set of 293 HD subjects whose ages of onset were known and sized their HD CAG repeats. These repeats accounted for 69% of the variance of age of onset when we used the most parsimonious model, which relates the logarithm of age of onset to a function of CAG repeat number. Since other familial factors have been proposed to influence the age of onset of HD, we have examined a number of candidate loci. The CAG repeat number on normal chromosomes, the delta2642 polymorphism in the HD gene, and apolipoprotein E genotypes did not affect the age of onset of HD. Although mitochondrial energy production defects in HD have led to suggestions that variants in the mitochondrial genome may be associated with clinical variability in HD, this suggestion was not supported by our preliminary experiments that examined the DdeI mitochondrial restriction fragment length polymorphism at position 10,394. Excitotoxicity has been a favored mechanism to explain the cell death in HD, particularly since intrastriatal injection of excitatory amino acids in animals creates HD-like pathology. Accordingly, we investigated the GluR6 kainate receptor. Of the variance in the age of onset of HD that was not accounted for by the CAG repeats, 13% could be attributed to GluR6 genotype variation. These data implicate GluR6-mediated excitotoxicity in the pathogenesis of HD and highlight the potential importance of this process in other polyglutamine repeat expansion diseases.

    Proceedings of the National Academy of Sciences of the United States of America 1997;94;8;3872-6

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

Cookies Policy | Terms and Conditions. This site is hosted by Edinburgh University and the Genes to Cognition Programme.