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Am J Hum Genet. 2017 Jun 1;100(6):969-977. doi: 10.1016/j.ajhg.2017.05.009.

Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination.

Author information

1
Department of Molecular Neuroscience, University College London, London WC1N 3BG, UK; Department of Neurology and Neurosurgery, Institute of Emergency Medicine, Toma Ciorbă 1, 2052 Chisinau, Republic of Moldova. Electronic address: v.chelban@ucl.ac.uk.
2
Developmental Genetics Unit, Department of Genetics, King Faisal Specialist Hospital and Research Center, MBC 03, PO Box 3354, Riyadh 11211 Saudi Arabia.
3
Department of Molecular Neuroscience, University College London, London WC1N 3BG, UK.
4
Department of Clinical and Experimental Epilepsy, University College London, London WC1N 3BG, UK.
5
Reta Lila Weston Research Laboratories, Institute of Neurology, University College London, London WC1N 3BG, UK; Department of Medical and Molecular Genetics, King's College London, Guy's Hospital, SE1 9RT London, UK.
6
Reta Lila Weston Research Laboratories, Institute of Neurology, University College London, London WC1N 3BG, UK; Department of Information and Communications Engineering, University of Murcia, Campus Espinardo, 30100 Murcia, Spain.
7
Department of Brain Repair and Rehabilitation, University College London, London WC1N 3BG, UK.
8
See Document S1 for list of collaborators.
9
Department of Pediatrics, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
10
Department of Molecular Neuroscience, University College London, London WC1N 3BG, UK; Neurogenetics Laboratory, The National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK.
11
Department of Clinical and Experimental Epilepsy, University College London, London WC1N 3BG, UK; Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520-8002.
12
Developmental Genetics Unit, Department of Genetics, King Faisal Specialist Hospital and Research Center, MBC 03, PO Box 3354, Riyadh 11211 Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12371, Saudi Arabia. Electronic address: falkuraya@kfshrc.edu.sa.

Abstract

Progressive limb spasticity and cerebellar ataxia are frequently found together in clinical practice and form a heterogeneous group of degenerative disorders that are classified either as pure spastic ataxia or as complex spastic ataxia with additional neurological signs. Inheritance is either autosomal dominant or autosomal recessive. Hypomyelinating features on MRI are sometimes seen with spastic ataxia, but this is usually mild in adults and severe and life limiting in children. We report seven individuals with an early-onset spastic-ataxia phenotype. The individuals come from three families of different ethnic backgrounds. Affected members of two families had childhood onset disease with very slow progression. They are still alive in their 30s and 40s and show predominant ataxia and cerebellar atrophy features on imaging. Affected members of the third family had a similar but earlier-onset presentation associated with brain hypomyelination. Using a combination of homozygozity mapping and exome sequencing, we mapped this phenotype to deleterious nonsense or homeobox domain missense mutations in NKX6-2. NKX6-2 encodes a transcriptional repressor with early high general and late focused CNS expression. Deficiency of its mouse ortholog results in widespread hypomyelination in the brain and optic nerve, as well as in poor motor coordination in a pattern consistent with the observed human phenotype. In-silico analysis of human brain expression and network data provides evidence that NKX6-2 is involved in oligodendrocyte maturation and might act within the same pathways of genes already associated with central hypomyelination. Our results support a non-redundant developmental role of NKX6-2 in humans and imply that NKX6-2 mutations should be considered in the differential diagnosis of spastic ataxia and hypomyelination.

KEYWORDS:

NKX6-2; ataxia; genetic; leukodystrophy; recessive; spasticity

PMID:
28575651
PMCID:
PMC5473715
DOI:
10.1016/j.ajhg.2017.05.009
[Indexed for MEDLINE]
Free PMC Article
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