DCCmutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome

Abstract

The deleted in colorectal cancer (DCC) gene encodes the netrin‐1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss‐of‐function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss‐of‐function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss‐of‐function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype–phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus‐specific LOVD (https://databases.lovd.nl/shared/genes/DCC).

DRAXIN regulates interhemispheric fissure remodelling to influence the extent of corpus callosum formation

“…The developmental basis of varied severity and expressivity of CCD in humans has to date been unclear. For example, humans with pathogenic variants in the DRAXIN receptor, DCC, display a range of CC phenotypes and associated HC malformations even across family members carrying the same pathogenic variant (Jamuar et al, 2017;Marsh et al, 2017;Marsh et al, 2018). Dcc mutant mice, which carry loss of function mutations, do not recapitulate the phenotypic variability observed in humans (Fazeli et al, 1997;Finger et al, 2002;Fothergill et al, 2013).…”

“…Draxin is a promising candidate to explain CCD in the BTBR x C57 N2 mouse, since Draxin knockout mice display CCD (Ahmed et al, 2011;Islam et al, 2009). Moreover, mutations in the gene encoding the DRAXIN receptor, DCC, are also associated with CCD in mice and humans (Fazeli et al, 1997;Finger et al, 2002;Fothergill et al, 2013;Jamuar et al, 2017;Marsh et al, 2018;Marsh et al, 2017). We generated in situ riboprobes for wildtype and mutant Draxin using mRNA isolated from C57 and BTBR mice, respectively, and examined the mRNA expression in the BTBR…”

The DCC receptor regulates astroglial development essential for telencephalic morphogenesis and corpus callosum formation

“…Having established that DCC signalling rearranges the cytoskeleton of astroglial-like cells, and that the P3 domain of DCC is crucial for this function, we next investigated whether DCC mutant receptors from humans with dysgenesis of the CC affected this function. Site directed mutagenesis was performed to introduce missense mutations into the pCAG-DCC:TDTOMATO expression vector in order to model mutated DCC receptors found in six families with previously reported cases of complete or partial agenesis of the CC (p.Met743Leu, p.Val754Met, p.Ala893Thr, p.Val793Gly, p.Gly805Glu, p.Met1217Val;p.Ala1250Thr;Marsh et al, 2017;Marsh et al, 2018;Figure 8A and S6C). We further included two artificial mutant receptors that were previously shown to perturb NTN1 binding and chemoattraction (p.Val848Arg, p.His857Ala; Finci et al, 2014).…”

“…Indeed, NTN1-DCC signalling attracts pioneering callosal axons towards the midline and attenuates chemorepulsive signaling in neocortical callosal axons ex vivo to facilitate crossing the midline (Fothergill et al, 2014). Heterozygous and homozygous DCC pathogenic variants also result in human callosal dysgenesis at high frequency (Jamuar et al, 2017;Marsh et al, 2018;Marsh et al, 2017) with an estimated incidence of 1 in 14 in unrelated individuals with callosal dysgenesis (Marsh et al, 2017), and Ntn1 and Dcc mouse mutants do not form a CC (Fazeli et al, 1997;Finger et al, 2002;Fothergill et al, 2014;Serafini et al, 1996). Instead of crossing the midline, callosal axons in Ntn1 and Dcc mutant mice form ipsilateral "Probst" bundles that run parallel to the midline (Fazeli et al, 1997;Finger et al, 2002;Fothergill et al, 2014;Ren et al, 2007;Serafini et al, 1996).…”

Identification of SMARCD1 as a syndromic intellectual disability gene that is required for memory and context-dependent regulation of neuronal genes in Drosophila

“…Libraries were sequenced on the Illumina HiSeq, and analysis was performed as described 31 . For individual 2, exome sequencing was performed as described in 32 (as for family 1 in that citation). For the individuals 3 and 4, exome sequencing was done as part of the DDD project.…”