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

TitleBiallelic Mutations in UNC80 Cause Persistent Hypotonia, Encephalopathy, Growth Retardation, and Severe Intellectual Disability.
Publication TypeJournal Article
Year of Publication2016
AuthorsStray-Pedersen, A, Cobben, J-M, Prescott, TE, Lee, S, Cang, C, Aranda, K, Ahmed, S, Alders, M, Gerstner, T, Aslaksen, K, Tétreault, M, Qin, W, Hartley, T, Jhangiani, SN, Muzny, DM, Tarailo-Graovac, M, van Karnebeek, CDM, Lupski, JR, Ren, D, Yoon, G
Corporate Authors,
JournalAm J Hum Genet
Volume98
Issue1
Pagination202-9
Date Published2016 Jan 7
ISSN1537-6605
KeywordsAdolescent, Alleles, Brain Diseases, Carrier Proteins, Child, Child, Preschool, Female, Growth Disorders, Humans, Intellectual Disability, Membrane Proteins, Muscle Hypotonia, Mutation, Severity of Illness Index
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.

DOI10.1016/j.ajhg.2015.11.004
Alternate JournalAm. J. Hum. Genet.
PubMed ID26708751
PubMed Central IDPMC4716670
Grant ListNS074257 / NS / NINDS NIH HHS / United States
R01 NS055293 / NS / NINDS NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States
NS055293 / NS / NINDS NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada
R01 NS074257 / NS / NINDS NIH HHS / United States