title: Genetic and functional analyses identify DISC1 as a novel callosal agenesis candidate gene.
abstract: Agenesis of the corpus callosum (AgCC) is a congenital brain malformation that occurs in approximately 1:1,000-1:6,000 births. Several syndromes associated with AgCC have been traced to single gene mutations; however, the majority of AgCC causes remain unidentified. We investigated a mother and two children who all shared complete AgCC and a chromosomal deletion at 1q42. We fine mapped this deletion and show that it includes Disrupted-in-Schizophrenia 1 (DISC1), a gene implicated in schizophrenia and other psychiatric disorders. Furthermore, we report a de novo chromosomal deletion at 1q42.13 to q44, which includes DISC1, in another individual with AgCC. We resequenced DISC1 in a cohort of 144 well-characterized AgCC individuals and identified 20 sequence changes, of which 4 are rare potentially pathogenic variants. Two of these variants were undetected in 768 control chromosomes. One of these is a splice site mutation at the 5' boundary of exon 11 that dramatically reduces full-length mRNA expression of DISC1, but not of shorter forms. We investigated the developmental expression of mouse DISC1 and find that it is highly expressed in the embryonic corpus callosum at a critical time for callosal formation. Taken together our results suggest a significant role for DISC1 in corpus callosum development.
authors: Department of Neurology, University of California San Francisco, San Francisco, California, USA.
authors: Nathan
authors: N
authors: Osbun
authors: Jiang
authors: J
authors: Li
authors: Mary C
authors: MC
authors: O'Driscoll
authors: Zoe
authors: Z
authors: Strominger
authors: Mari
authors: M
authors: Wakahiro
authors: Eric
authors: E
authors: Rider
authors: Polina
authors: P
authors: Bukshpun
authors: Elena
authors: E
authors: Boland
authors: Cailyn H
authors: CH
authors: Spurrell
authors: Wendy
authors: W
authors: Schackwitz
authors: Len A
authors: LA
authors: Pennacchio
authors: William B
authors: WB
authors: Dobyns
authors: Graeme C M
authors: GC
authors: Black
authors: Elliott H
authors: EH
authors: Sherr
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D061085:Agenesis of Corpus Callosum; D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D003337:Corpus Callosum / Q000196:embryology / Q000378:metabolism; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D014927:Wolff-Parkinson-White Syndrome / Q000235:genetics
chemical_list: C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins