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Cited by 81Fetal and Pediatric Neurological DisordersAxon Guidance and Neuronal SignalingGenetics and Neurodevelopmental Disorders

Biallelic mutations in human DCC cause developmental split-brain syndrome

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Jamuar, Saumya S, Schmitz-Abe, Klaus, D'Gama, Alissa M, Drottar, Marie, Chan, Wai-Man, Peeva, Maya, Servattalab, Sarah, Lam, Anh-Thu N +18 more·2017·Nature Genetics
DOI 10.1038/ng.3804PMC PMC5374027
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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.

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  • Loss-of-function mutations in DCC cause severe neurodevelopmental syndromes involving loss of midline commissural tracts and diffuse disorganization of white matter tracts.

    “Loss-of-function mutations in DCC cause severe neurodevelopmental syndromes involving loss of midline commissural tracts and diffuse disorganization of white matter tracts (Bendriem and Ross, 2017; Jamuar et al., 2017; Marsh et al., 2017).”

    From Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders (2019) · cites this paper as Jamuar et al., 2017

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Authors
Jamuar, S. S., Schmitz-Abe, K., D'Gama, A. M., Drottar, M., Chan, W.-M., Peeva, M., Servattalab, S., Lam, A.-T. N., Delgado, M. R., Clegg, N. J., Zayed, Z. A., Dogar, M. A., Alorainy, I. A., Jamea, A. A., Abu-Amero, K., Griebel, M., Ward, W., Lein, E. S., Markianos, K., Barkovich, A. J., Robson, C. D., Grant, P. E., Bosley, T. M., Engle, E. C., Walsh, C. A., & Yu, T. W.
Affiliations
  • Boston Children's Hospital (US)
  • Texas Scottish Rite Hospital for Children (US)
  • King Faisal Specialist Hospital & Research Centre (SA)
  • Cleveland Clinic Abu Dhabi (AE)
  • King Saud University (SA)
  • Arkansas Children's Hospital (US)
  • Allen Institute for Brain Science (US)
  • University of California, San Francisco (US)
  • Johns Hopkins University (US)
  • Broad Institute (US)
Corresponding author
Yu, Timothy W
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2017-02-27
Volume
49
Issue
4
Pages
606-612
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.3804
PMC
PMC5374027
OpenAlex
W2594350203
Cited by
81
References
0
Citations by year
2026: 3 · 2025: 5 · 2024: 9 · 2023: 9 · 2022: 13 · 2021: 8 · 2020: 8 · 2019: 11 · 2018: 8 · 2017: 7
FWCI
10.16
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institute of Mental Health (R01MH083565)
  • National Eye Institute (R01EY012498)
  • National Institute of General Medical Sciences (T32GM007753, T32GM007226)
  • National Institute of Neurological Disorders and Stroke (R01NS035129, R01NS032457)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090255, P30HD018655)
Topics
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
DCC gene, split-brain syndrome, agenesis of the corpus callosum, brainstem malformation, horizontal gaze palsy, mirror movements, scoliosis, intellectual disability, axon guidance
MeSH terms
Brain, Central Nervous System, Female, Humans, Male, Intellectual Disability, Mutation, Neurons, Phenotype, Receptors, Cell Surface, Colorectal Neoplasms, Gene Expression Regulation, Developmental, Loss of Heterozygosity, Polymorphism, Single Nucleotide

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