Biallelic mutations in human DCC cause developmental split-brain syndrome.
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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 new human syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is 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 central nervous system (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. |
Year of Publication | 2017
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Journal | Nat Genet
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Volume | 49
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Issue | 4
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Pages | 606-612
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Date Published | 2017 Apr
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ISSN | 1546-1718
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DOI | 10.1038/ng.3804
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PubMed ID | 28250456
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PubMed Central ID | PMC5374027
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Links | |
Grant list | R01 NS032457 / NS / NINDS NIH HHS / United States
R01 MH083565 / MH / NIMH NIH HHS / United States
T32 GM007226 / GM / NIGMS NIH HHS / United States
R01 EY012498 / EY / NEI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
P30 HD018655 / HD / NICHD NIH HHS / United States
Howard Hughes Medical Institute / United States
R01 NS035129 / NS / NINDS NIH HHS / United States
U54 HD090255 / HD / NICHD NIH HHS / United States
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