Alternative titles; symbols
HGNC Approved Gene Symbol: UNC80
Cytogenetic location: 2q34 Genomic coordinates (GRCh38) : 2:209,771,832-209,999,296 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q34 | Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 | 616801 | Autosomal recessive | 3 |
The UNC80 gene encodes a large protein necessary for the stability and function of the NALCN (611549) sodium leak channel and for bridging NALCN to UNC79 (616884) to form a functional complex (summary by Shamseldin et al., 2016).
By sequencing clones obtained from an adult hippocampus cDNA library, Nagase et al. (2001) cloned C2ORF21, which they designated KIAA1843. The deduced protein contains 1,341 amino acids. RT-PCR ELISA detected C2ORF21 expression in adult and fetal brain and in all specific adult brain regions examined. Very low expression was detected in testis and pancreas, and no expression was detected in other adult and fetal tissues examined.
Jospin et al. (2007) cloned Unc80, the C. elegans ortholog of C2ORF21. The deduced protein contains 3,184 amino acids. Fluorescence-tagged Unc80 was highly expressed throughout the worm nervous system, as well as in other tissues.
Lu et al. (2009) cloned a mammalian UNC80 homolog from mouse brain. The UNC80 gene was predicted to encode a 371-kD protein with 96% identity with its human homolog.
Shamseldin et al. (2016) found that murine Unc80 was nearly exclusively expressed in the adult brain.
Perez et al. (2016) found expression of the UNC80 gene in multiple human tissues, with highest expression in the adrenal gland, prostate, testis, brain, and cerebellum.
By radiation hybrid analysis, Nagase et al. (2001) mapped the C2ORF21 gene to chromosome 2.
Gross (2018) mapped the UNC80 gene to chromosome 2q34 based on an alignment of the UNC80 sequence (GenBank BC136690) with the genomic sequence (GRCh38).
Jospin et al. (2007) found that C. elegans Unc80 was required for proper localization or stabilization of axonal NCA ion channel components, which are homologous to the vertebrate NALCN channel (611549).
Lu et al. (2009) showed that, in the mouse hippocampal and ventral tegmental area neurons, substance P (see 162320) and neurotensin (162650) activate a channel complex containing NALCN and the large protein UNC80. The activation of substance P through its G protein-coupled receptor TACR1 (162323) occurs by means of a unique mechanism: it does not require G protein activation but is dependent on Src family kinases. Lu et al. (2009) suggested that their findings identified NALCN as the cation channel activated by substance P receptor, and suggested that UNC80 and Src family kinases, rather than a G protein, are involved in the coupling from receptor to channel.
By immunoprecipitation analysis of mouse brain, Lu et al. (2010) found that Unc79 (616884) precipitated with Unc80 and Nalcn. Use of Nalcn -/- and Unc79 -/- mouse hippocampal neurons and transfection in human cell lines revealed that both Nalcn and Unc79 interacted directly with Unc80, but not with each other. Leak currents generated by Nalcn alone were insensitive to extracellular Ca(2+), and Unc80 provided Ca2+ sensitivity. Unc79 appeared to contribute to Ca2+ sensitivity of Nalcn currents by interacting with Unc80 and stabilizing Unc80 protein level. Inhibition of a Ca(2+)-sensitive G protein, possibly Casr (601199), countered Ca(2+) sensitivity of Nalcn currents. Unc79 -/- mice have disrupted breathing rhythms, fail to nurse, and die within the first days of life. Lu et al. (2010) found that Unc79 -/- hippocampal neurons showed normal Nalcn-dependent Na+ leak currents, but their leak currents were largely insensitive to changes in extracellular Ca(2+) concentration. Overexpression of Unc80 could bypass the requirement for Unc79 and rescue extracellular Ca(2+) sensitivity. Lu et al. (2010) concluded that extracellular Ca(2+) sensitivity of Nalcn leak currents is dependent upon Unc80, but that Unc79 may contribute to Ca(2+) sensitivity, possibly by stabilizing Unc80 protein levels.
In 4 girls from 3 unrelated families with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2; 616801), Stray-Pedersen et al. (2016) identified biallelic mutations on the UNC80 gene (612636.0001-612636.0004). The mutations, which were found by exome sequencing, were predicted to result in a loss of function. In vitro studies of 1 of the mutations (P1700S; 612636.0001) showed that it was expressed normally and associated with UNC79 and NALCN (611549), but patch-clamp recording studies showed that the variant had significantly reduced NALCN currents compared to wildtype.
In 6 living children from 4 unrelated consanguineous families with IHPRF2, Shamseldin et al. (2016) identified 3 different homozygous mutations in the UNC80 gene (612636.0005-613636.0007). Two of the mutations were truncating and 1 was missense; functional studies of the variant and studies of patient cells were not performed.
In 7 children from 2 distantly related consanguineous Bedouin families with IHPRF2, Perez et al. (2016) identified a homozygous nonsense mutation in the UNC80 gene (R51X; 612636.0008). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder. Western blot analysis of cells transfected with the mutant transcript showed absence of the UNC80 protein, consistent with a loss of function.
In a 4-year-old girl, born of consanguineous Iraqi parents, with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2; 616801), Stray-Pedersen et al. (2016) identified a homozygous c.5098C-T transition (c.5098C-T, NM_032504.1) in exon 32 of the UNC80 gene, resulting in a pro1700-to-ser (P1700S) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP, 1000 Genomes Project, or ExAC databases, but was present in heterozygous state in 1 of over 3,000 in-house control exomes. The unaffected mother carried the mutation; DNA from the father was not available. Transfection of the mutation into the mouse gene and HEK293T cells showed that it was expressed normally and associated with UNC79 (616884) and NALCN (611549), but patch-clamp recording studies showed that the variant had significantly reduced NALCN currents compared to wildtype, consistent with a loss of function.
In a 4-year-old girl, born of consanguineous Moroccan parents, with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2; 616801), Stray-Pedersen et al. (2016) identified a homozygous c.7607G-C transversion (c.7607G-C, NM_032504.1) in the last nucleotide of exon 50, predicted to result in either an arg2536-to-thr (R2536T) substitution at a highly conserved residue or a splicing defect. Splicing studies could not be performed because UNC80 is not expressed in peripheral leukocytes and additional tissue was not available from the patient. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and was not found in the dbSNP, 1000 Genomes Project, or ExAC databases. The mutation was predicted to result in a loss of function.
In 2 sisters, born of unrelated Norwegian parents, with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2; 616801), Stray-Pedersen et al. (2016) identified compound heterozygous mutations in the UNC80 gene: a 1-bp deletion (c.2033delA, NM_032504.1) in exon 13, resulting in a frameshift and premature termination (Asn678ThrfsTer15) and a c.7757T-A transversion in exon 51, resulting in a leu2586-to-ter (L2586X; 612636.0004) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, and were not found in the dbSNP, 1000 Genomes Project, or ExAC databases. Functional studies and studies in patient cells were not performed, but the mutations were predicted to result in a loss of function.
For discussion of the c.7757T-A transversion (c.7757T-A, NM_032504.1) in exon 51 of the UNC80 gene, resulting in a leu2586-to-ter (L2586X) substitution, that was found in compound heterozygous state in a patient with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2; 616801) by Stray-Pedersen et al. (2016), see 612636.0003.
In 3 children from 2 unrelated consanguineous Saudi Arabian families with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2; 616801), Shamseldin et al. (2016) identified a homozygous c.3793C-T transition (c.3793C-T, NM_032504.1) in the UNC80 gene, resulting in an arg1265-to-ter (R1265X) substitution. The mutation, which was found by a combination of autozygosity mapping and exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the 2 families. It was not found in the ExAC database or in 650 Saudi Arabian control exomes. Functional studies of the variant and studies of patient cells were not performed.
In a 7-year-old girl, born of consanguineous Saudi Arabian parents, with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2; 616801), Shamseldin et al. (2016) identified a homozygous c.1078C-T transition (c.1078C-T, NM_032504.1) in the UNC80 gene, resulting in an arg360-to-ter (R360X) substitution. The mutation, which was found by exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. It was not found in the ExAC database or in 650 Saudi Arabian control exomes. Functional studies of the variant and studies of patient cells were not performed.
In 2 sisters, born of consanguineous Egyptian parents, with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2; 616801), Shamseldin et al. (2016) identified a homozygous c.565G-A transition (c.565G-A, NM_032504.1) in the UNC80 gene, resulting in a val189-to-met (V189M) substitution. The mutation, which was found by exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. It was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed.
In 7 children from 2 distantly related consanguineous Bedouin families with infantile hypotonia with psychomotor retardation and characteristic facies-2 (IHPRF2; 616801), Perez et al. (2016) identified a homozygous c.151C-T transition in exon 3 of the UNC80 gene, resulting in an arg51-to-ter (R51X) substitution. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. It was found in the heterozygous state in 1 of 150 ethnically-matched controls. Western blot analysis of cells transfected with the mutant transcript showed absence of the UNC80 protein, consistent with a loss of function.
Gross, M. B. Personal Communication. Baltimore, Md. 4/10/2018.
Jospin, M., Watanabe, S., Joshi, D., Young, S., Hamming, K., Thacker, C., Snutch, T. P., Jorgensen, E. M., Schuske, K. UNC-80 and the NCA ion channels contribute to endocytosis defects in synaptojanin mutants. Curr. Biol. 17: 1595-1600, 2007. [PubMed: 17825559] [Full Text: https://doi.org/10.1016/j.cub.2007.08.036]
Lu, B., Su, Y., Das, S., Wang, H., Wang, Y., Liu, J., Ren, D. Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80. Nature 457: 741-744, 2009. [PubMed: 19092807] [Full Text: https://doi.org/10.1038/nature07579]
Lu, B., Zhang, Q., Wang, H., Wang, Y., Nakayama, M., Ren, D. Extracellular calcium controls background current and neuronal excitability via an UNC79-UNC80-NALCN cation channel complex. Neuron 68: 488-499, 2010. [PubMed: 21040849] [Full Text: https://doi.org/10.1016/j.neuron.2010.09.014]
Nagase, T., Nakayama, M., Nakajima, D., Kikuno, R., Ohara, O. Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 8: 85-95, 2001. [PubMed: 11347906] [Full Text: https://doi.org/10.1093/dnares/8.2.85]
Perez, Y., Kadir, R., Volodarsky, M., Noyman, I., Flusser, H., Shorer, Z., Gradstein, L., Birnbaum, R. Y., Birk, O. S. UNC80 mutation causes a syndrome of hypotonia, severe intellectual disability, dyskinesia and dysmorphism, similar to that caused by mutations in its interacting cation channel NALCN. J. Med. Genet. 53: 397-402, 2016. [PubMed: 26545877] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103352]
Shamseldin, H. E., Faqeih, E., Alasmari, A., Zaki, M. S., Gleeson, J. G., Alkuraya, F. S. Mutations in UNC80, encoding part of the UNC79-UNC80-NALCN channel complex, cause autosomal-recessive severe infantile encephalopathy. Am. J. Hum. Genet. 98: 210-215, 2016. [PubMed: 26708753] [Full Text: https://doi.org/10.1016/j.ajhg.2015.11.013]
Stray-Pedersen, A., Cobben, J.-M., Prescott, T. E., Lee, S., Cang, C., Aranda, K., Ahmed, S., Alders, M., Gerstner, T., Aslaksen, K., Tetreault, M., Qin, W., and 10 others. Biallelic mutations in UNC80 cause persistent hypotonia, encephalopathy, growth retardation, and severe intellectual disability. Am. J. Hum. Genet. 98: 202-209, 2016. [PubMed: 26708751] [Full Text: https://doi.org/10.1016/j.ajhg.2015.11.004]