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Am J Hum Genet. 2016 Jan 7;98(1):202-9. doi: 10.1016/j.ajhg.2015.11.004. Epub 2015 Dec 17.

Biallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability.

Author information

  • 1Department of Molecular and Human Genetics, Baylor College of Medicine and the Baylor-Hopkins Center for Mendelian Genomics, Houston, TX 77030, USA; Norwegian National Newborn Screening Program, Oslo University Hospital, Oslo 0424, Norway.
  • 2Department of Pediatrics, Academic Medical Center University Hospital, Amsterdam 1105 AZ, the Netherlands.
  • 3Department of Medical Genetics, Oslo University Hospital, Oslo 0424, Norway.
  • 4Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 5Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada.
  • 6Department of Clinical Genetics, AMC University Hospital, Amsterdam 1105 AZ, the Netherlands.
  • 7Department of Pediatrics, Sørlandet Hospital, Arendal 4838, Norway.
  • 8Department of Pediatrics, Sørlandet Hospital, Kristiansand 4615, Norway.
  • 9Department of Human Genetics, McGill University and Genome Québec Innovation Center, Montréal, QC H3A 0G4, Canada.
  • 10The Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada.
  • 11Department of Molecular and Human Genetics, Baylor College of Medicine and the Baylor-Hopkins Center for Mendelian Genomics, Houston, TX 77030, USA; Baylor College of Medicine Human Genome Sequencing Center, Houston, TX 77030, USA.
  • 12Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
  • 13Department of Pediatrics and Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
  • 14Department of Molecular and Human Genetics, Baylor College of Medicine and the Baylor-Hopkins Center for Mendelian Genomics, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor College of Medicine Human Genome Sequencing Center, Houston, TX 77030, USA.
  • 15Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: dren@sas.upenn.edu.
  • 16Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada; Division of Neurology, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada. Electronic address: grace.yoon@utoronto.ca.

Abstract

Ion channel proteins are required for both the establishment of resting membrane potentials and the generation of action potentials. Hundreds of mutations in genes encoding voltage-gated ion channels responsible for action potential generation have been found to cause severe neurological diseases. In contrast, the roles of voltage-independent "leak" channels, important for the establishment and maintenance of resting membrane potentials upon which action potentials are generated, are not well established in human disease. UNC80 is a large component of the NALCN sodium-leak channel complex that regulates the basal excitability of the nervous system. Loss-of-function mutations of NALCN cause infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF). We report four individuals from three unrelated families who have homozygous missense or compound heterozygous truncating mutations in UNC80 and persistent hypotonia, encephalopathy, growth failure, and severe intellectual disability. Compared to control cells, HEK293T cells transfected with an expression plasmid containing the c.5098C>T (p.Pro1700Ser) UNC80 mutation found in one individual showed markedly decreased NALCN channel currents. Our findings demonstrate the fundamental significance of UNC80 and basal ionic conductance to human health.

PMID:
26708751
PMCID:
PMC4716670
DOI:
10.1016/j.ajhg.2015.11.004
[PubMed - indexed for MEDLINE]
Free PMC Article
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