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.

708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits

“…10, 11, 13, 14, 16, 17, 23, 46, 70 (Figure 1; Supplementary Figure S3; Supplementary Tables S2 and S3). …”

Hippocampal commissure defects in crosses of four inbred mouse strains with absent corpus callosum

“…Mutations of the doublecortin ( DCX ) gene alter hippocampal development, reduces the HC, and gives rise to total absence of the CC in both mice and humans (Kappeler et al, 2007), and the anatomical defects appear to be very similar to what is seen in I/Ln and BTBR mice, although the AC is somewhat reduced in size and disorganized. A deletion of the DISC1 gene in humans is associated with absence of the CC (Osbun et al, 2011). The mouse Disc1 gene is highly expressed in the embyonic CC (Osbun et al , 2011), and mice with a targeted mutation of Disc1 also show reduced CC (Shen et al , 2008).…”

“…A deletion of the DISC1 gene in humans is associated with absence of the CC (Osbun et al, 2011). The mouse Disc1 gene is highly expressed in the embyonic CC (Osbun et al , 2011), and mice with a targeted mutation of Disc1 also show reduced CC (Shen et al , 2008). A deletion in the Disc1 gene on mouse chromosome 8 is intriguing because it is found in certain 129 substrains (Koike et al, 2006) as well as strain BTBR (Clapcote & Roder, Mouse Gene Informatics MGI 3699429), but the deletion is also found in strain LP/J that shows a normal corpus callosum (unpublished data from Munn et al, 2011).…”

ROUNDABOUT Receptors

“…Interestingly, srGAP3 can bind to both Robo1 and Robo2 and a knockout mouse for srGAP3 showed mild guidance defects of spinal cord commissural axons at the fl oor plate as in the Robo2 KO (though ventral funiculus axons do not express high levels Robo2) (Bacon et al 2011 ). Finally and quite interestingly DISC1 mutants have similar callosal defects as seen in Slit-Robo mutants and DISC1 has been known to be implicated in psychiatric disorders ranging from bipolar disorder to schizophrenia (Millar et al 2000 ;Osbun et al 2011 ).…”