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Link to original content: http://omim.org/entry/603342
Alternative titles; symbols
DO: 0070078;
Cytogenetic location: 11q14-q21 Genomic coordinates (GRCh38) : 11:77,400,001-97,400,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q14-q21 | {?Schizophrenia} | 181500 | Autosomal dominant | 2 |
For a phenotypic description of schizophrenia, see 181500.
Among 282 pedigrees in the MRC Cytogenetics Registry, Edinburgh, with familial autosomal anomalies, St Clair et al. (1990) found 1 with 23 cases of mental and/or behavioral disorders. Of the 77 family members available for cytogenetic analysis, 34 were found to carry a balanced translocation t(1;11)(q43;q21). Psychiatric diagnoses had been recorded for 16 of the 34 members with the translocation compared with only 5 of the 43 without it. Lod scores (against chance linkage of the translocation with mental illness) were greatest when the mental disorders in the phenotype were restricted to schizophrenia, schizoaffective disorder, recurrent major depression, and adolescent conduct and emotional disorders. St Clair et al. (1990) suggested that the 11q21-q22 region may be the site of gene(s) predisposing to major mental illness. Earlier, Smith et al. (1989) had observed cosegregation of affective illness with an 11q22.3-9p22 translocation. A third independent observation of a chromosome 11 translocation associated with major psychosis was made by Holland and Gosden (1990), who reported a balanced 6q14.2;11q25 translocation segregating with a psychotic illness in a 3-generation family. The proband had had mild intellectual impairment and behavioral problems since childhood. In adult life he developed a psychosis that met DSM III criteria for schizoaffective disorder. His mother, who also carried the translocation, met DSM III criteria for paranoid schizophrenia. The proband's sister, who committed suicide, was a presumptive translocation carrier because both of her twin daughters carried the translocation. Although one of the twins had made a suicide attempt, neither had a psychotic illness at age 20. The proband's maternal uncle and aunt both carried the translocation, but neither had developed a psychosis by age 72 and 69, respectively. Several members of the family suffered psychiatric illness, but did not carry the translocation.
Su et al. (1993) failed to find cosegregation of allelic variation at the D2 dopamine receptor locus (DRD2; 126450) and 5 surrounding loci with schizophrenia in 112 small- to moderate-sized Irish families containing 2 or more members affected with schizophrenia or schizoaffective disorder. Wang et al. (1993) failed to find evidence for linkage to schizophrenia in 12 multiplex pedigrees using 16 markers spanning 130 cM on chromosome 11q that included all 3 reported translocations. Mulcrone et al. (1995) found no evidence for a schizophrenia susceptibility locus using 11q13-q24 markers in 5 multiplex Israeli families. Kalsi et al. (1995) obtained strongly negative lod scores for linkage in 23 multiplex kindreds using markers that spanned a 70-cM region of 11q, including both translocation sites and the candidate genes tyrosinase (TYR; 606933) and DRD2.
Fletcher et al. (1993) used immunomagnetic beads directed against human surface antigens to prepare translocation hybrids bracketing TYR and D11S388, which flank the translocation breakpoint at 11q21. Muir et al. (1995) prepared a library from microdissection of the schizophrenia-related translocation at 11q21. The same group (Evans et al., 1995) constructed a 3-cM YAC contig across a schizophrenia-related translocation breakpoint which they described on 11q14.3. In a case-control association study using polymorphic markers D1S1621 and D11S931 spanning the 11q14.3 schizophrenia-associated breakpoint, Wilson-Annan et al. (1997) found no evidence for a susceptibility locus.
Devon and Porteous (1997) demonstrated that the potential candidate gene encoding metabotropic glutamate receptor 5A lies at least 850 kb from the 11q21 schizophrenia-associated breakpoint. Levinson et al. (1998) found evidence (P less than 0.05) for a schizophrenia susceptibility locus on chromosome 11 (D11S2002) in a genomewide scan using 310 microsatellite DNA markers with average spacing of 11 cM in 269 individuals, 126 of whom had schizophrenia-related psychoses, from 43 pedigrees.
Yamada et al. (2004) performed a genomewide linkage disequilibrium analysis in 119 Japanese schizophrenic pedigrees (357 individuals) using 444 microsatellite markers and found that 14 markers demonstrated significant transmission distortion. By extended transmission of disequilibrium analysis on 80 independent complete trios (68 derived from initial pedigrees and 12 newly recruited trios), they identified 2 markers with continued association, D11S987 on 11q13.3 (p = 0.00009) and D16S423 on 16p13.3 (P = 0.002). After adding 26 new markers from the 11q11-q13 locus, 3-marker haplotype analysis showed evidence of association with schizophrenia, yielding a global p value of 0.022 for the most significant haplotype.
Chromosome 11q22 was first implicated in schizophrenia in a linkage study of 2 Japanese pedigrees in which positive lod scores between 1.0 and 1.5 were reported with marker D11S35 (Nanko et al., 1992). This was confirmed in a separate study of a large Canadian pedigree, in which a maximum lod score of 3.4 was obtained using the same genetic marker (Maziade et al., 1995). Gurling et al. (2001) also reported linkage at 11q23.3. Choudhury et al. (2007) reported fine mapping of a susceptibility gene in the 11q22-q24 region, determined on the basis of a University College London (UCL) sample of 496 cases and 488 supernormal controls. Confirmation was then performed by the study of an Aberdeen example consisting of 858 cases and 591 controls. Seven microsatellite or SNP markers localized within or near the FXYD6 (606683) gene showed empirically significant allelic associations with schizophrenia in the UCL sample. Several haplotypes were also found to be associated with schizophrenia; for example, Hap-F21, comprising markers rs10790212, rs4938445, and rs497768, was found to be associated with schizophrenia by a global permutation test (P = 0.002). Positive markers in the UCL sample were genotyped in the Aberdeen sample; 2 of these SNPs (rs4938445, rs497768) were found to be associated with schizophrenia in the Scottish sample (p = 0.044 and 0.037, respectively). Hap-F21 was associated with schizophrenia in the Aberdeen sample also (empirical P = 0.013). The FXYD6 gene encodes a protein called phosphohippolin that is highly expressed in regions of the brain and thought to be involved in schizophrenia. The protein functions by modulating the kinetic properties of Na,K-ATPase to the specific physiologic requirements of the tissue. Choudhury et al. (2007) concluded that etiologic basepair changes in FXYD6 or in associated promoter/control regions are likely to cause abnormal function or expression of phosphohippolin and increase genetic susceptibility to schizophrenia.
Choudhury, K., McQuillin, A., Puri, V., Pimm, J., Datta, S., Thirumalai, S., Krasucki, R., Lawrence, J., Bass, N. J., Quested, D., Crombie, C., Fraser, G., Walker, N., Nadeem, H., Johnson, S., Curtis, D., St. Clair, D., Gurling, H. M. D. A genetic association study of chromosome 11q22-24 in two different samples implicates the FXYD6 gene, encoding phosphohippolin, in susceptibility to schizophrenia. Am. J. Hum. Genet. 80: 664-672, 2007. [PubMed: 17357072] [Full Text: https://doi.org/10.1086/513475]
Devon, R. S., Porteous, D. J. Physical mapping of a glutamate receptor gene in relation to a balanced translocation associated with schizophrenia in a large Scottish family. Psychiat. Genet. 7: 165-169, 1997. [PubMed: 9460801]
Evans, K. L., Brown, J., Shibasaki, Y., Devon, R. S., He, L., Arveiler, B., Christie, S., Maule, J. C., Baillie, D., Slorach, E. M., Anderson, S. M., Gosden, J. R., Petit, J., Weith, A., Gosden, C. M., Blackwood, D. H. R., St. Clair, D. M., Muir, W. J., Brookes, A. J., Porteous, D. J. A contiguous clone map over 3 Mb on the long arm of chromosome 11 across a balanced translocation associated with schizophrenia. Genomics 28: 420-428, 1995. [PubMed: 7490076] [Full Text: https://doi.org/10.1006/geno.1995.1170]
Fletcher, J. M., Evans, K., Baillie, D., Byrd, P., Hanratty, D., Leach, S., Julier, C., Gosden, J. R., Muir, W., Porteous, D. J., St. Clair, D., van Heyningen, V. Schizophrenia-associated chromosome 11q21 translocation: identification of flanking markers and development of chromosome 11q fragment hybrids as cloning and mapping resources. Am. J. Hum. Genet. 52: 478-490, 1993. [PubMed: 8383424]
Gurling, H. M. D., Kalsi, G., Brynjolfson, J., Sigmundsson, T., Sherrington, R., Mankoo, B. S., Read, T., Murphy, P., Blaveri, E., McQuillin, A., Petursson, H., Curtis, D. Genomewide genetic linkage analysis confirms the presence of susceptibility loci for schizophrenia, on chromosomes 1q32.2, 5q33.2, and 8p21-22 and provides support for linkage to schizophrenia, on chromosomes 11q23.3-24 and 20q12.1-11.23. Am. J. Hum. Genet. 68: 661-673, 2001. Note: Erratum: Am. J. Hum. Genet. 68: 1075 only, 2001. [PubMed: 11179014] [Full Text: https://doi.org/10.1086/318788]
Holland, T., Gosden, C. A balanced chromosomal translocation partially co-segregating with psychotic illness in a family. Psychiat. Res. 32: 1-8, 1990. [PubMed: 2349309] [Full Text: https://doi.org/10.1016/0165-1781(90)90129-s]
Kalsi, G., Mankoo, B. S., Curtis, D., Brynjolfsson, J., Read, T., Sharma, T., Murphy, P., Petursson, H., Gurling, H. M. D. Exclusion of linkage of schizophrenia to the gene for the dopamine D2 receptor (DRD2) and chromosome 11q translocation sites. Psychol. Med. 25: 531-537, 1995. [PubMed: 7480434] [Full Text: https://doi.org/10.1017/s0033291700033456]
Levinson, D. F., Mahtani, M. M., Nancarrow, D. J., Brown, D. M., Kruglyak, L., Kirby, A., Hayward, N. K., Crowe, R. R., Andreasen, N. C., Black, D. W., Silverman, J. M., Endicott, J., and 10 others. Genome scan of schizophrenia. Am. J. Psychiat. 155: 741-750, 1998. [PubMed: 9619145] [Full Text: https://doi.org/10.1176/ajp.155.6.741]
Maziade, M., Raymond, V., Cliche, D., Fournier, J. P., Caron, C., Garneau, Y., Nicole, L., Marcotte, P., Couture, C., Simard, C. Linkage results on 11q21-22 in Eastern Quebec pedigrees densely affected by schizophrenia. Am. J. Med. Genet. 60: 522-528, 1995. [PubMed: 8825888] [Full Text: https://doi.org/10.1002/ajmg.1320600607]
Muir, W. J., Gosden, C. M., Brookes, A. J., Fantes, J., Evans, K. L., Maguire, S. M., Stevenson, B., Boyle, S., Blackwood, D. H. R., St. Clair, D. M., Porteous, D. J., Weith, A. Direct microdissection and microcloning of a translocation breakpoint region, t(1;11)(q42.2;q21), associated with schizophrenia. Cytogenet. Cell Genet. 70: 35-40, 1995. [PubMed: 7736785] [Full Text: https://doi.org/10.1159/000133986]
Mulcrone, J., Whatley, S. A., Marchbanks, R., Wildenauer, D., Altmark, D., Daoud, H., Gur, E., Ebstein, R. P., Lerer, B. Genetic linkage analysis of schizophrenia using chromosome 11q13-24 markers in Israeli pedigrees. Am. J. Med. Genet. 60: 103-108, 1995. [PubMed: 7485242] [Full Text: https://doi.org/10.1002/ajmg.1320600204]
Nanko, S., Gill, M., Owen, M., Takazawa, N., Moridaira, J., Kazamatsuri, H. Linkage study of schizophrenia with markers on chromosome 11 in two Japanese pedigrees. Jpn. J. Psychiat. Neurol. 46: 155-159, 1992.
Smith, M., Wasmuth, J., McPherson, J. D., Wagner, C., Grandy, D., Civelli, O., Potkin, S., Litt, M. Cosegregation of an 11q22.3-9p22 translocation with affective disorder: proximity of the dopamine D2 receptor gene relative to the translocation breakpoint. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A220 only, 1989.
St Clair, D., Blackwood, D., Muir, W., Carothers, A., Walker, M., Spowart, G., Gosden, C., Evans, H. J. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 336: 13-16, 1990. [PubMed: 1973210] [Full Text: https://doi.org/10.1016/0140-6736(90)91520-k]
Su, Y., Burke, J., O'Neill, F. A., Murphy, B., Nie, L., Kipps, B., Bray, J., Shinkwin, R., Nuallain, M. N., MacLean, C. J., Walsh, D., Diehl, S. R., Kendler, K. S. Exclusion of linkage between schizophrenia and the D(2) dopamine receptor gene region of chromosome 11q in 112 Irish multiplex families. Arch. Gen. Psychiat. 50: 205-211, 1993. [PubMed: 8439241] [Full Text: https://doi.org/10.1001/archpsyc.1993.01820150055005]
Wang, Z. W., Black, D., Andreasen, N. C., Crowe, R. R. A linkage study of chromosome 11q in schizophrenia. Arch. Gen. Psychiat. 50: 212-216, 1993. [PubMed: 8439242] [Full Text: https://doi.org/10.1001/archpsyc.1993.01820150062006]
Wilson-Annan, J. C., Blackwood, D. H., Muir, W., Millar, J. K., Porteous, D. J. An allelic association study of two polymorphic markers in close proximity to a balanced translocation t(1:11) that co-segregates with mental illness. Psychiat. Genet. 7: 171-174, 1997. [PubMed: 9460802]
Yamada, K., Iwayama-Shigeno, Y., Yoshida, Y., Toyota, T., Itokawa, M., Hattori, E., Shimizu, H., Yoshikawa, T. Family-based association study of schizophrenia with 444 markers and analysis of a new susceptibility locus mapped to 11q13.3. Am. J. Med. Genet. Neuropsychiat. Genet. 127B: 11-19, 2004. [PubMed: 15108173] [Full Text: https://doi.org/10.1002/ajmg.b.20166]