G2Cdb::Human Disease report

Disease id
D00000193
Name
Alzheimer's disease
Nervous system disease
yes

Genes (4)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00002371 CALM1
calmodulin 1 (phosphorylase kinase, delta)
Y (9237482) Single nucleotide polymorphism (SNP) N
G00002098 GRIN1
glutamate receptor, ionotropic, N-methyl D-aspartate 1
Y (15030408) Splice variant (SpVar) Y
G00001394 MAPK8IP1
mitogen-activated protein kinase 8 interacting protein 1
Y (12740599) Single nucleotide polymorphism (SNP) Y
G00000030 NOS1
nitric oxide synthase 1 (neuronal)
Y (12210288) Dinucleotide polymorphism (DNP) N

References

  • Selective loss of NMDA receptor NR1 subunit isoforms in Alzheimer's disease.

    Hynd MR, Scott HL and Dodd PR

    Department of Biochemistry, University of Queensland, Australia.

    Previous work had shown that the ratio of NMDA receptor NR1 subunit mRNA transcripts containing an N-terminal splice cassette to those that do not is markedly lower in regions of the Alzheimer's disease (AD) brain that are susceptible to pathological damage, compared with spared regions in the same cases or homotropic regions in controls. To elucidate the origins of this difference in proportionate expression, we measured the absolute levels of each of the eight NR1 transcripts by quantitative internally standardized RT-PCR assay. Expression of transcripts with the cassette was strongly attenuated in susceptible regions of Alzheimer's brain, whereas expression of non-cassette transcripts differed little from that in controls. The expression of other NR1 splice variants was not associated with pathology relevant to disease status, although some combinations of splice cassettes were well maintained in AD cases. The population profile of NR1 transcripts in occipital cortex differed from the profiles in other brain regions studied. Western analysis confirmed that the expression of protein isoforms containing the N-terminal peptide was very low in susceptible areas of the Alzheimer's brain. Cells that express NR1 subunits with the N-terminal cassette may be selectively vulnerable to toxicity in AD.

    Journal of neurochemistry 2004;89;1;240-7

  • Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease.

    Helbecque N, Abderrahamani A, Meylan L, Riederer B, Mooser V, Miklossy J, Delplanque J, Boutin P, Nicod P, Haefliger JA, Cottel D, Amouyel P, Froguel P, Waeber G and Abderrhamani A

    Institut National de la Santé et de la Recherche Médicale U508, Pasteur Institute, Lille, France.

    Islet-brain1 (IB1) or c-Jun NH2 terminal kinase interacting protein-1 (JIP-1), the product of the MAPK8IP1 gene, functions as a neuronal scaffold protein to allow signalling specificity. IB1/JIP-1 interacts with many cellular components including the reelin receptor ApoER2, the low-density lipoprotein receptor-related protein (LRP), kinesin and the Alzheimer's amyloid precursor protein. Coexpression of IB1/JIP-1 with other components of the c-Jun NH2 terminal-kinase (JNK) pathway activates the JNK activity; conversely, selective disruption of IB1/JIP-1 in mice reduces the stress-induced apoptosis of neuronal cells. We therefore hypothesized that IB1/JIP-1 is a risk factor for Alzheimer's disease (AD). By immunocytochemistry, we first colocalized the presence of IB1/JIP-1 with JNK and phosphorylated tau in neurofibrillary tangles. We next identified a -499A>G polymorphism in the 5' regulatory region of the MAPK8IP1 gene. In two separate French populations the -499A>G polymorphism of MAPK8IP1 was not associated with an increased risk to AD. However, when stratified on the +766C>T polymorphism of exon 3 of the LRP gene, the IB1/JIP-1 polymorphism was strongly associated with AD in subjects bearing the CC genotype in the LRP gene. The functional consequences of the -499A>G polymorphism of MAPK8IP1 was investigated in vitro. In neuronal cells, the G allele increased transcriptional activity and was associated with an enhanced binding activity. Taken together, these data indicate that the increased transcriptional activity in the presence of the G allele of MAPK8IP1 is a risk factor to the onset of in patients bearing the CC genotype of the LRP gene.

    Funded by: Medical Research Council: G0000477

    Molecular psychiatry 2003;8;4;413-22, 363

  • No association between the neuronal nitric oxide synthase gene polymorphism and Alzheimer Disease.

    Liou YJ, Hong CJ, Liu HC, Liu CY, Liu TY, Chen IC and Tsai SJ

    Section of Psychiatry, Yu-Li Veterans Hospital, Hualien, Taiwan, Republic of China.

    Nitric oxide synthase (NOS) has been implicated in the pathogenesis of Alzheimer disease (AD). To examine the role of the neuronal NOS (nNOS) gene in AD, patients (n = 139) and control subjects (n = 101) were genotyped for the nNOS dinucleotide polymorphism. No association was demonstrated for AD and this particular nNOS polymorphism.

    American journal of medical genetics 2002;114;6;687-8

  • Mutation analysis of chromosome 19 calmodulin (CALM3) gene in Alzheimer's disease patients.

    Ibarreta D, Tao J, Parrilla R and Ayuso MS

    Department of Physiopathology and Human Molecular Genetics, Centro de Investigaciones Biológicas (CSIC), Velázquez, Madrid, Spain.

    The calcium buffering capacity of lymphoblasts from patients suffering of late onset Alzheimer's disease (AD) has been reported to be diminished. Calmodulin is a calcium binding protein codified by three genes, one of them (CALM3) maps to chromosome 19, nearby a gene, apoE, associated with late onset AD. In this study we screened for structural changes in the CALM3 gene from AD patients by PCR-SSCP analysis. We observed several point mutations in the intronic flanking regions of exons 3 and 4 of CALM 3 gene. However, we failed to detect any structural changes in the regions encoding the calcium binding domains of this gene. Similar results were obtained by RT-PCR analysis of CALM3 transcripts from AD patients carrying apoE epsilon4 allele. It is concluded that structural alterations in the CALM3 gene are not associated with the altered Ca2+ homeostasis shown by lymphoblasts from these patients.

    Neuroscience letters 1997;229;3;157-60

Literature (4)

Pubmed - human_disease

  • No association between the neuronal nitric oxide synthase gene polymorphism and Alzheimer Disease.

    Liou YJ, Hong CJ, Liu HC, Liu CY, Liu TY, Chen IC and Tsai SJ

    Section of Psychiatry, Yu-Li Veterans Hospital, Hualien, Taiwan, Republic of China.

    Nitric oxide synthase (NOS) has been implicated in the pathogenesis of Alzheimer disease (AD). To examine the role of the neuronal NOS (nNOS) gene in AD, patients (n = 139) and control subjects (n = 101) were genotyped for the nNOS dinucleotide polymorphism. No association was demonstrated for AD and this particular nNOS polymorphism.

    American journal of medical genetics 2002;114;6;687-8

  • Mutation analysis of chromosome 19 calmodulin (CALM3) gene in Alzheimer's disease patients.

    Ibarreta D, Tao J, Parrilla R and Ayuso MS

    Department of Physiopathology and Human Molecular Genetics, Centro de Investigaciones Biológicas (CSIC), Velázquez, Madrid, Spain.

    The calcium buffering capacity of lymphoblasts from patients suffering of late onset Alzheimer's disease (AD) has been reported to be diminished. Calmodulin is a calcium binding protein codified by three genes, one of them (CALM3) maps to chromosome 19, nearby a gene, apoE, associated with late onset AD. In this study we screened for structural changes in the CALM3 gene from AD patients by PCR-SSCP analysis. We observed several point mutations in the intronic flanking regions of exons 3 and 4 of CALM 3 gene. However, we failed to detect any structural changes in the regions encoding the calcium binding domains of this gene. Similar results were obtained by RT-PCR analysis of CALM3 transcripts from AD patients carrying apoE epsilon4 allele. It is concluded that structural alterations in the CALM3 gene are not associated with the altered Ca2+ homeostasis shown by lymphoblasts from these patients.

    Neuroscience letters 1997;229;3;157-60

Pubmed - other

  • Selective loss of NMDA receptor NR1 subunit isoforms in Alzheimer's disease.

    Hynd MR, Scott HL and Dodd PR

    Department of Biochemistry, University of Queensland, Australia.

    Previous work had shown that the ratio of NMDA receptor NR1 subunit mRNA transcripts containing an N-terminal splice cassette to those that do not is markedly lower in regions of the Alzheimer's disease (AD) brain that are susceptible to pathological damage, compared with spared regions in the same cases or homotropic regions in controls. To elucidate the origins of this difference in proportionate expression, we measured the absolute levels of each of the eight NR1 transcripts by quantitative internally standardized RT-PCR assay. Expression of transcripts with the cassette was strongly attenuated in susceptible regions of Alzheimer's brain, whereas expression of non-cassette transcripts differed little from that in controls. The expression of other NR1 splice variants was not associated with pathology relevant to disease status, although some combinations of splice cassettes were well maintained in AD cases. The population profile of NR1 transcripts in occipital cortex differed from the profiles in other brain regions studied. Western analysis confirmed that the expression of protein isoforms containing the N-terminal peptide was very low in susceptible areas of the Alzheimer's brain. Cells that express NR1 subunits with the N-terminal cassette may be selectively vulnerable to toxicity in AD.

    Journal of neurochemistry 2004;89;1;240-7

  • Islet-brain1/C-Jun N-terminal kinase interacting protein-1 (IB1/JIP-1) promoter variant is associated with Alzheimer's disease.

    Helbecque N, Abderrahamani A, Meylan L, Riederer B, Mooser V, Miklossy J, Delplanque J, Boutin P, Nicod P, Haefliger JA, Cottel D, Amouyel P, Froguel P, Waeber G and Abderrhamani A

    Institut National de la Santé et de la Recherche Médicale U508, Pasteur Institute, Lille, France.

    Islet-brain1 (IB1) or c-Jun NH2 terminal kinase interacting protein-1 (JIP-1), the product of the MAPK8IP1 gene, functions as a neuronal scaffold protein to allow signalling specificity. IB1/JIP-1 interacts with many cellular components including the reelin receptor ApoER2, the low-density lipoprotein receptor-related protein (LRP), kinesin and the Alzheimer's amyloid precursor protein. Coexpression of IB1/JIP-1 with other components of the c-Jun NH2 terminal-kinase (JNK) pathway activates the JNK activity; conversely, selective disruption of IB1/JIP-1 in mice reduces the stress-induced apoptosis of neuronal cells. We therefore hypothesized that IB1/JIP-1 is a risk factor for Alzheimer's disease (AD). By immunocytochemistry, we first colocalized the presence of IB1/JIP-1 with JNK and phosphorylated tau in neurofibrillary tangles. We next identified a -499A>G polymorphism in the 5' regulatory region of the MAPK8IP1 gene. In two separate French populations the -499A>G polymorphism of MAPK8IP1 was not associated with an increased risk to AD. However, when stratified on the +766C>T polymorphism of exon 3 of the LRP gene, the IB1/JIP-1 polymorphism was strongly associated with AD in subjects bearing the CC genotype in the LRP gene. The functional consequences of the -499A>G polymorphism of MAPK8IP1 was investigated in vitro. In neuronal cells, the G allele increased transcriptional activity and was associated with an enhanced binding activity. Taken together, these data indicate that the increased transcriptional activity in the presence of the G allele of MAPK8IP1 is a risk factor to the onset of in patients bearing the CC genotype of the LRP gene.

    Funded by: Medical Research Council: G0000477

    Molecular psychiatry 2003;8;4;413-22, 363

© 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).

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