Biallelic mutations in human DCC cause developmental split-brain syndrome

Abstract

Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a novel human syndrome in which these commissures are widely disrupted, causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the axon guidance receptor Deleted in Colorectal Carcinoma (DCC), a gene previously implicated in congenital mirror movements when mutated in the heterozygous state, but whose biallelic loss-of-function human phenotype has not been reported. Structural MRI and diffusion tractography demonstrated broad disorganization of white matter tracts throughout the human CNS including loss of all commissural tracts at multiple levels of the neuraxis. Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white matter projections throughout the human CNS.

Making Dopamine Connections in Adolescence

“…This strategy has uncovered a critical role for DCC signalling in shaping mesocorticolimbic dopamine circuitry. Notably, Dcc haploinsufficiency also occurs in humans [54–58]. …”

“…Dcc haploinsufficiency has been found in several family lineages worldwide [54–58]. There has been great interest in the neuroanatomical and behavioural implications of Dcc haploinsufficiency in humans, however its implications for mesocorticolimbic development and related psychiatric disorders have so far remained unexamined.…”

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

“…For instance, it remains to be determined whether mutant DCC proteins are stably expressed and trafficked to the plasma membrane or aberrantly sequestered in the cytoplasm like mutant NTN1 proteins (Méneret et al., ). However, absence of the DSBS phenotype in an individual with a biallelic p.(Gln691Lys) missense mutation suggests that these mutant proteins may retain some residual function (Jamuar et al., ).…”

“…Biallelic, DCC mutations leading to predicted LoF are associated with DSBS, a complex syndrome associated with a broad disorganization of white‐matter tracts throughout the CNS (Jamuar et al., ). The features of DSBS include absence of all commissures (including the CC, anterior, and posterior), brainstem defects (including hypoplasia of the pons and midbrain), horizontal gaze palsy and progressive scoliosis with a variable age of onset (Figure ).…”

“…DCC is expressed by commissural axons and binds NTN1, a secreted protein encoded by the NTN1 gene (MIM# 601614), which functions both locally and diffusely as a bifunctional guidance cue (Blasiak, Kilinc, & Lee, ; Keino‐Masu et al., ; Kennedy, Serafini, de la Torre, & Tessier‐Lavigne, ). Both DCC and NTN1 are expressed throughout the developing mouse and human brain, with distinct but complementary spatial and temporal expression patterns (Harter et al., ; Jamuar et al., ; Ren et al., ; Shu, Valentino, Seaman, Cooper, & Richards, ). DCC is required for the transduction of NTN1‐induced attractive and long‐range repulsive signaling in the coordinated outgrowth and guidance of commissural axons that cross the anatomical midline of the body (Chan et al., ; Hong et al., ; Keino‐Masu et al., ).…”