title: Biallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability.
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.
authors.affiliation: Department 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.
authors.forename: Asbjørg
authors.initials: A
authors.lastname: Stray-Pedersen
authors.affiliation: Department of Pediatrics, Academic Medical Center University Hospital, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Jan-Maarten
authors.initials: JM
authors.lastname: Cobben
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, Oslo 0424, Norway.
authors.forename: Trine E
authors.initials: TE
authors.lastname: Prescott
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sora
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Chunlei
authors.initials: C
authors.lastname: Cang
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Aranda
authors.affiliation: Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON M5G 1X8, Canada.
authors.forename: Sohnee
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Department of Clinical Genetics, AMC University Hospital, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Marielle
authors.initials: M
authors.lastname: Alders
authors.affiliation: Department of Pediatrics, Sørlandet Hospital, Arendal 4838, Norway.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Gerstner
authors.affiliation: Department of Pediatrics, Sørlandet Hospital, Kristiansand 4615, Norway.
authors.forename: Kathinka
authors.initials: K
authors.lastname: Aslaksen
authors.affiliation: Department of Human Genetics, McGill University and Genome Québec Innovation Center, Montréal, QC H3A 0G4, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Tétreault
authors.affiliation: The Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada.
authors.forename: Wen
authors.initials: W
authors.lastname: Qin
authors.affiliation: The Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 8L1, Canada.
authors.forename: Taila
authors.initials: T
authors.lastname: Hartley
authors.affiliation: Department 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.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Department 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.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Maja
authors.initials: M
authors.lastname: Tarailo-Graovac
authors.affiliation: Department of Pediatrics and Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Clara D M
authors.initials: CD
authors.lastname: van Karnebeek
authors.affiliation: Department 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.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: dren@sas.upenn.edu.
authors.forename: Dejian
authors.initials: D
authors.lastname: Ren
authors.affiliation: Division 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.
authors.forename: Grace
authors.initials: G
authors.lastname: Yoon
mesh_terms: D000293:Adolescent; D000483:Alleles; D001927:Brain Diseases / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006130:Growth Disorders / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D009123:Muscle Hypotonia / Q000235:genetics*; D009154:Mutation; D012720:Severity of Illness Index
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C544680:Unc80 protein, human