title: A mannosyltransferase gene at 11q23 is disrupted by a translocation breakpoint that co-segregates with bipolar affective disorder in a small family.
abstract: Bipolar affective disorder (BPAD) is a complex neuropsychiatric disease characterized by extreme mood swings. Genetic influences affect the disease susceptibility substantially, yet the underlying mechanisms are unknown. We previously described a pedigree in which all five individuals with BPAD and one individual with recurrent major depression were carriers of a reciprocal chromosomal translocation t(9;11)(p24;q23). Gene content analyses of the breakpoint junctions revealed disruption of a gene (DIBD1 ) at 11q23, a genomic region that has also been implicated in schizophrenia and Tourette syndrome. DIBD1 is predicted to encode a mannosyltransferase similar to Saccaromyces cerevisiae Alg9p of the protein N-glycosylation pathway. The in-born errors of protein N-glycosylation cause congenital disorders of glycosylation in humans. DIBD1 shows uniform expression in the tested subregions of the brain by Northern analysis. Sequence analysis revealed four intragenic single nucleotide polymorphisms. The valine residue at V289I was conserved in other eukaryotic species, whereas its frequency was approximately 65% in humans. We performed linkage and linkage disequilibrium analyses in two NIMH bipolar pedigree series using four tightly linked simple tandem repeat polymorphisms (STRPs) and the V289I. These analyses overall failed to support a role for DIBD1 in disease susceptibility. The most-significant finding was a lod score of 1.18 (P=0.0098), obtained by an intronic STRP D11S5025, in the subset of 22 multiplex pedigrees. In conclusion, we found that a mannosyltransferase gene at 11q23 is disrupted by a translocation breakpoint co-segregating with BPAD in a family. However, its role in the disease susceptibility remains unconfirmed.
authors.affiliation: Department of Psychiatry, The University of Pittsburgh Medical Center, Pennsylvania, USA. baysalbe@msx.upmc.edu
authors.forename: Bora E
authors.initials: BE
authors.lastname: Baysal
authors.forename: Joan E
authors.initials: JE
authors.lastname: Willett-Brozick
authors.forename: Judith A
authors.initials: JA
authors.lastname: Badner
authors.forename: Winston
authors.initials: W
authors.lastname: Corona
authors.forename: Robert E
authors.initials: RE
authors.lastname: Ferrell
authors.forename: Vishwajit L
authors.initials: VL
authors.lastname: Nimgaonkar
authors.forename: Sevilla D
authors.initials: SD
authors.lastname: Detera-Wadleigh
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006031:Glycosylation; D006801:Humans; D008297:Male; D008364:Mannosyltransferases / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017386:Sequence Homology, Amino Acid; D014178:Translocation, Genetic
chemical_list: D008565:Membrane Proteins; C469962:ALG9 protein, human; D008364:Mannosyltransferases