Abstract
Bipolar affective disorder is a genetically complex psychiatric disorder with a population prevalence of approximately 1%. We have previously reported cosegregation of bipolar affective disorder and Darier's disease, a dominant skin disorder with a neuropsychiatric component. The gene for Darier's disease was mapped to chromosome 12q23–q24.1 and linkage studies by us and others have subsequently implicated this region as harbouring a susceptibility gene for bipolar affective disorder. In this study we have investigated the Darier's disease gene ATP2A2, the calcium pumping ATPase SERCA2, as a potential susceptibility gene for bipolar disorder under the hypothesis that variations in SERCA2 have pleiotropic effects in brain. Support for this hypothesis comes from clinical evidence of neuropsychiatric abnormalities in Darier's disease, genetic data produced in our study showing non-random clustering of missense mutations in ATP2A2 in neuropsychiatric Darier patients, and functional data demonstrating the role of SERCA2 in intracellular calcium regulation. In a panel of 15 unrelated bipolar patients from multiply affected families showing increased allele sharing at markers in the 12q23–q24.1 region, we performed mutational screening of the ATP2A2 coding sequence, promoter regions, and 3′ untranslated region and identified six sequence variations. These were analysed in a large sample of bipolar patients (n = 324) and control subjects (n = 327). Analysis of allele and genotype distributions for all six variations, and of haplotype frequencies showed no evidence for the involvement of ATP2A2 in producing susceptibility to bipolar disorder.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Craddock N, Jones I . Genetics of bipolar disorder J Med Genet 1999 36: 585–594
Craddock N, Khodel V, Van Eerdewegh P, Reich T . Mathematical limits of multilocus models: the genetic transmission of bipolar disorder Am J Hum Genet 1995 57: 690–702
Craddock N, Owen M, Burge S, Kurian B, Thomas P, Mcguffin P . Familial cosegregation of major affective disorder and Darier's disease (keratosis follicularis) Br J Psychiatry 1994 164: 355–358
Jones I, Owen MJ, Craddock N . Further evidence for the familial cosegregation of major affective disorder and Darier's disease Mol Psychiatry 1999 4: S73
Craddock N, Dawson E, Burge S, Parfitt L, Mant B, Roberts Q et al. The gene for Darier's disease maps to chromosome 12q23–q24.1 Hum Mol Genet 1993 2: 1941–1943
Bashir R, Munro CS, Mason S, Stephenson A, Rees JL, Strachan T . Localisation of a gene for Darier's disease Hum Mol Genet 1993 2: 1937–1939
Wakem P, Ikeda S, Haake A, Polakowska R, Ewing N, Sarret Y et al. Localization of the Darier disease gene to a 2 cM portion of 12q23–24.1 J Invest Dermatol 1996 106: 365–367
Richard G, Wright AR, Harris S, Doyle SZ, Korge B, Mazzanti C et al. Fine mapping of the Darier's disease locus on chromosome 12q J Invest Dermatol 1994 103: 665–668
Kennedy JL, Berg D, Bassett AS, Roy R, King N, Perkins M . Genetic linkage for Darier disease (keratosis follicularis) Am J Med Genet 1995 55: 307–310
Dawson E, Parfitt E, Roberts Q, Daniels J, Lim L, Sham P et al. Linkage studies of bipolar disorder in the region of the Darier's disease gene on chromosome 12q23–24.1 Am J Med Genet 1995 60: 94–102
Barden N, Plante M, Rochette D . Genome wide microsatellite marker linkage study of Bipolar affective disorders in a very large pedigree derived from a homogenous population in Quebec points to a susceptibility locus on chromosome 12 Psychiatr Genet 1996 6: 145–146
Ewald H, Degn B, Mors O, Kruse TA . Significant linkage between bipolar affective disorder and chromosome 12q24 Psychiatr Genet 1998 8: 131–140
Clark RDJ, Hammer CJ, Patterson SD . A cutaneous disorder (Darier's disease) evidently exacerbated by lithium carbonate Psychosomatics 1986 27: 800–801
Milton GP, Peck GL, Fu JJL, Digiovanna JJ, Nordlund JJ, Thomas JH et al. Exacerbation of Darier's disease by lithium carbonate J Am Acad Dermatol 1990 23: 926
Burge SM, Wilkinson JD . Darier-White disease: a review of the clinical features in 163 patients J Am Acad Dermatol 1992 27: 40–50
Getzler NA, Flint A . Keratosis follicularis. A study of one family Arch Dermatol 1966 93: 545–549
Hellwig B, Hesslinger B, Walden J . Darier's disease and psychosis Psychiatry Res 1996 64: 205–207
Medansky RS, Woloshin AA . Darier's disease. An evaluation of its neuropsychiatric component Arch Dermatol 1961 84: 482–484
Peck GL, Kraemer KH, Wetzel B, Klinger WG, Cohen K . Cornifying Darier's disease—a unique variant Arch Dermatol 1976 112: 495–503
Svendsen IB, Albrectsen B . The prevalence of dyskeratosis follicularis (Darier's disease) in Denmark Acta Derm Venereol 1959 39: 256–269
Denicoff KD, Lehman ZA, Rubinow DR, Schmidt PJ, Peck GL . Suicidal ideation in Darier's disease J Am Acad Dermatol 1990 22: 196–198
Burge S . Darier's disease—the clinical features and pathogenesis Clin Exp Dermatol 1994 19: 193–205
Sakuntabhai A, Ruiz-Perez V, Carter S, Jacobsen N, Burge S, Monk S et al. Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease Nat Genet 1999 21: 271–277
Sakuntabhai A, Burge S, Monk S, Hovnanian A . Spectrum of novel ATP2A2 mutations in patients with Darier's disease Hum Mol Genet 1999 8: 1611–1619
RuizPerez VL, Carter SA, Healy E, Todd C, Rees JL, Steijlen PM et al. ATP2A2 mutations in Darier's disease: variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class Hum Mol Genet 1999 8: 1621–1630
Jacobsen NJO, Lyons I, Hoogendoorn B, Burge S, Kwok PY, O'Donovan MC et al. ATP2A2 mutations in Darier's disease and their relationship to neuropsychiatric phenotypes Hum Mol Genet 1999 8: 1631–1636
Lytton J, Maclennan DH . Molecular cloning of cDNAs from human kidney coding for two alternatively spliced products of the cardiac Ca2+ ATPase gene J Biol Chem 1988 263: 15024–15031
Pozzan T, Rizzuto R, Volpe P, Meldolesi J . Molecular and cellular physiology of intracellular calcium stores Physiol Rev 1994 74: 595–636
Maclennan DH, Brandl CJ, Korczak B, Green NM . Amino acid sequence of a Ca2+/Mg2+ dependent ATPase from rabbit muscle sarcoplasmic reticulum, deduced from its complementary DNA sequence Nature 1985 316: 696–700
Baba-Aissa F, Van Den Bosch L, Wuytack F, Raeymaekers L, Casteels R . Regulation of the sarco/endoplasmic reticulum Ca2+-ATPase SERCA2 gene transcript in neuronal cells Mol Brain Res 1998 55: 92–100
Baba-Aissa F, Raeymaekers L, Wuytack F, Dode L, Casteels R . Distribution and isoform diversity of the organellar Ca2+ pumps in the brain Mol Chem Neuropathol 1998 33: 199–208
Berridge MJ, Bootman MD, Lipp P . Calcium—a life and death signal Nature 1998 395: 645–648
Emamghoreishi M, Schlichter L, Li PP, Parikh S, Sen J, Kamble A et al. High intracellular calcium concentrations in transformed lymphoblasts from subjects with bipolar I disorder Am J Psychiatry 1997 154: 976–982
Berk M . Lamotrigine and the treatment of mania in bipolar disorder Eur Neuropsychiatry 1999 9: S119–S123
Dubovsky SL . Calcium antagonists in manic depressive illness Neuropsychobiology 1993 27: 184–192
Atack JR, Broughton HB, Pollack SJ . Inositol monophosphatase—a putative target for Li+ in the treatment of bipolar disorder Trends Neurosci 1995 18: 343–349
Jope RS, Song L, Li PP, Young LT, Kish SJ, Pacheco MA et al. The phosphoinositide signal transduction system is impaired in bipolar affective disorder brain J Neurochem 1996 66: 2402–2409
Los GV, Artemenko IP, Hokin LE . Time dependent effects of lithium on the agonist stimulated accumulation of 2nd messenger inositol 1,4,5-trisphosphate in SH-SY5Y human neuroblastoma cells Biochem J 1995 311: 225–232
Soares JC, Dippold CS, Mallinger AG . Platelet membrane phosphatidylinositol-4,5-bisphosphate alterations in bipolar disorder—evidence from a single case study Psychiatry Res 1997 69: 197–202
Hibbeln JR, Palmer JW, Davis JM . Are disturbances in lipid protein interactions by phospholipase A2 a predisposing factor in affective illness Biol Psychiatry 1989 25: 945–961
Wankerl M, Boheler KR, Fiszman MY, Schwartz K . Molecular cloning and analysis of the human sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2) gene promoter J Mol Cell Cardiol 1996 28: 2139–2150
Culbertson MR . RNA surveillance. Unforeseen consequences for gene expression, inherited genetic disorders and cancer Trends Genet 1999 15: 74–80
Jones A, Austin JA, Hansen N, Hoogendoorn B, Oefner PJ, Cheadle JP et al. Optimal temperature selection for mutation detection by denaturing high performance liquid chromatography and comparison to SSCP and heteroduplex analysis Clin Chem 1999 45: 1133–1140
American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders American Psychiatric Association: Washington DC 1994
Endicott J, Spitzer RL . The schedule for affective disorders and schizophrenia Arch Gen Psychiatry 1978 35: 837–844
Wing JK, Babor T, Brugha T et al. SCAN: schedules for clinical assessment in neuropsychiatry Arch Gen Psychiatry 1990 4: 589–593
Oefner PJ, Underhill PA . Searching candidate genes for mutations. In: Dracopoli NC, Haines JL, Korf BR, Moir DT, Morton CC, Seidman CE et al (eds) Current Protocols in Human Genetics Wiley: New York 1998 7.10.1–7.10.12
O'Donovan MC, Oefner PJ, Roberts SC, Austin JA, Guy C, Hoogendoorn B et al. Blind analysis of denaturing high performance liquid chromatography as a tool for mutation detection Genomics 1998 52: 44–49
Arinami T, Itokawa M, Enguchi H, Tagaya H, Yano S, Shimizu H et al. Association of dopamine D2 receptor molecular variant with schizophrenia Lancet 1994 343: 703–704
Sham PC, Curtis D . Monte-Carlo tests for associations between disease and alleles at highly polymorphic loci Ann Hum Genet 1995 59: 97–105
Acknowledgements
This work was funded by the Wellcome Trust. Ian Jones is a Wellcome Trust Research Fellow in Mental Health and Nick Craddock is a Wellcome Trust Senior Research Fellow in Clinical Sciences.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Jacobsen, N., Franks, E., Elvidge, G. et al. Exclusion of the Darier's disease gene, ATP2A2, as a common susceptibility gene for bipolar disorder. Mol Psychiatry 6, 92–97 (2001). https://doi.org/10.1038/sj.mp.4000774
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.mp.4000774
Keywords
This article is cited by
-
Morbus Darier und Depression – besteht eine genetische Verbindung?
Der Nervenarzt (2007)
-
A neuronal nitric oxide synthase (NOS-I) haplotype associated with schizophrenia modifies prefrontal cortex function
Molecular Psychiatry (2006)
-
A genome-wide scan points to a susceptibility locus for bipolar disorder on chromosome 12
Molecular Psychiatry (2005)
-
Evidence for familial cosegregation of major affective disorder and genetic markers flanking the gene for Darier's disease
Molecular Psychiatry (2002)
-
Manic-depression genes and the new millennium: poised for discovery
Molecular Psychiatry (2002)