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Hum Mutat. 2018 Jan;39(1):23-39. doi: 10.1002/humu.23361. Epub 2017 Nov 11.

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

Marsh APL1,2, Edwards TJ3,4, Galea C5, Cooper HM3, Engle EC6,7,8,9,10,11, Jamuar SS6,7,8,12,13, Méneret A14,15, Moutard ML16,17,18, Nava C14,19, Rastetter A14, Robinson G20, Rouleau G21,22, Roze E14,15, Spencer-Smith M23,24, Trouillard O14, Billette de Villemeur T16,17,25,26, Walsh CA6,7,8,9,11,12, Yu TW6,11,12; IRC5 Consortium, Heron D17,19, Sherr EH27, Richards LJ3,28, Depienne C14,19,29,30, Leventer RJ2,31,32, Lockhart PJ1,2.

Author information

1
Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
2
Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
3
Queensland Brain Institute, The University of Queensland, St Lucia, Brisbane, Australia.
4
Faculty of Medicine, The University of Queensland, Herston, Brisbane, Australia.
5
Drug Delivery, Disposition and Dynamics (D4), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
6
Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts.
7
Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts.
8
Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts.
9
Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
10
Department of Ophthalmology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
11
Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts.
12
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
13
Department of Paediatrics, KK Women's and Children's Hospital, Paediatric Academic Clinical Programme, Duke-NUS Medical School, Singapore, Singapore.
14
INSERM, U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
15
Département de Neurologie, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.
16
Service de Neuropédiatrie, AP-HP, Hôpital Trousseau, Paris, France.
17
UPMC, GRC ConCer-LD, Sorbonne Université, Paris, France.
18
Centre de référence "Neurogénétique", Paris, France.
19
Département de Génétique, AP-HP, Hôpital de la Pitié-Salpêtrière, Paris, France.
20
Neuropsychology Research Unit, School of Psychology, The University of Queensland, Brisbane, Queensland, Australia.
21
Department of Neurology and Neurosurgery, McGill University Health Center, Montreal, Quebec, Canada.
22
Montreal Neurological Institute and Hospital, McGill University, Montréal, Quebec, Canada.
23
Clinical Sciences, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
24
School of Psychological Sciences and Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Clayton Campus, Clayton, Victoria, Australia.
25
Centre de Référence "déficiences intellectuelles de causes rares", Paris, France.
26
INSERM U1141, Paris, France.
27
Department of Neurology, UCSF Benioff Children's Hospital, San Francisco, California.
28
The University of Queensland, School of Biomedical Sciences, St Lucia, Brisbane, Australia.
29
Département de Médicine translationnelle et Neurogénétique, IGBMC, CNRS UMR 7104, INSERM U964, Université de Strasbourg, Illkirch, France.
30
Laboratoires de génétique, Institut de génétique médicale d'Alsace, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
31
Neuroscience Research Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
32
Department of Neurology, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.

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).

KEYWORDS:

ACC; DCC; NTN1; Netrin-1; agenesis of the corpus callosum; axon guidance; developmental split brain syndrome; horizontal gaze palsy with progressive scoliosis; mirror movements; mutation

PMID:
29068161
PMCID:
PMC5722687
DOI:
10.1002/humu.23361
[Indexed for MEDLINE]
Free PMC Article

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