Disruption of a brain transcription factor, NPAS3, is associated with schizophrenia and learning disability.
A mother and daughter diagnosed with schizophrenia and schizophrenia co-morbid with mild learning disability, respectively, possess a balanced reciprocal translocation t(9,14)(q34.2;q13). Fluorescence in situ hybridization (FISH) with YAC, BAC, and cosmid probes indicate that the chromosome 14q13 breakpoint disrupts a large gene, NPAS3, encoding a CNS expressed transcription factor of the basic helix-loop-helix PAS (bHLH-PAS) gene family. By analogy with other members of the bHLH-PAS family, the putative truncated protein generated from the disrupted gene locus may have a dominant negative effect. The 14q13 region was previously identified by a linkage study of an inherited neurodegenerative condition, idiopathic basal ganglia calcification (IBGC or Fahr syndrome, OMIM:213600/606656), which is often co-morbid with psychosis. Sequencing of the gene in a third patient diagnosed with IBGC, schizophrenia, and mild learning disability did not reveal functional mutations.
Pickard
Ben S
BS
Department of Psychiatry, University of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Morningside Park, UK. ben.pickard@ed.ac.uk
Malloy
M P
MP
Porteous
D J
DJ
Blackwood
D H R
DH
Muir
W J
WJ
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D001921:Brain / Q000378:metabolism; D019457:Chromosome Breakage / Q000235:genetics; D025063:Chromosome Disorders / Q000235:genetics / Q000473:pathology; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D005192:Family Health; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007859:Learning Disabilities / Q000473:pathology*; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012559:Schizophrenia / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C502963:NPAS3 protein, human