Alternative titles; symbols
HGNC Approved Gene Symbol: HNRNPU
Cytogenetic location: 1q44 Genomic coordinates (GRCh38) : 1:244,850,297-244,864,543 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q44 | Developmental and epileptic encephalopathy 54 | 617391 | Autosomal dominant | 3 |
The HNRNPU gene encodes a highly conserved protein that binds RNAs and mediates different aspects of their metabolism and transport (summary by Hamdan et al., 2014).
Heterogeneous nuclear ribonucleoproteins (hnRNPs) associate with nascent RNA polymerase II transcripts to form hnRNP complexes and are thought to influence the structure of hnRNA and to participate in pre-mRNA processing. Kiledjian and Dreyfuss (1992) isolated a cDNA for the largest of the major hnRNP proteins, an abundant nuclear phosphoprotein called hnRNP U, by immunoscreening of a HeLa cell cDNA library. The 3.2-kb HNRNPU cDNA encodes a putative protein of 806 amino acids with a calculated molecular mass of 88.9 kD. The authors found no homology to any known protein sequences. The predicted protein has an N-terminus rich in acidic amino acids, a putative nuclear localization signal, an NTP-binding site consensus sequence, a glycine-rich C terminus, and multiple potential casein and histone kinase phosphorylation and N-linked glycosylation sites. By testing deletion constructs, the authors determined that the RNA-binding region of the putative protein is located near the C-terminus, in a glycine-rich region termed U-gly. After confirming that this region can confer RNA-binding activity on a nonnucleic acid-binding protein, Kiledjian and Dreyfuss (1992) narrowed the RNA-binding region, which contains a cluster of RGG repeats, to 26 amino acids.
Fackelmayer and Richter (1994) isolated a cDNA clone for HNRNPU by immunoscreening of a cDNA expression library with polyclonal antibodies to scaffold attachment factor A (SAFA), a human nuclear protein with high affinity for scaffold-attached region DNA, and confirmed that SAFA and HNRNPU are identical. By Northern blot analysis, the authors detected 2 mRNAs of 3.9 and 3.1 kb. They also isolated 2 classes of cDNAs which varied in length at their 3-prime end due to alternative polyadenylation. Both mRNAs were present in all tissues tested in comparable amounts.
By screening a cDNA library for host genes or gene fragments able to interfere with infection by HIV-1 particles, Valente and Goff (2006) identified the N-terminal portion of HNRNPU as having potent anti-HIV-1 activity. Expression of the fragment encoding the N-terminal 86 amino acids blocks wildtype HIV-1 replication by targeting the 3-prime long-terminal repeat of the virus and preventing the accumulation of viral mRNA transcripts in the cytoplasm. Valente and Goff (2006) proposed that there is a pathway critical for HIV-1 mRNA export and that it can be blocked without impairing cell viability.
In a 33-year-old man (patient T162) with developmental and epileptic encephalopathy-54 (DEE54; 617391), Carvill et al. (2013) identified a heterozygous nonsense mutation in the HNRNPU gene (Y805X; 602869.0001). The mutation was not present in the mother; DNA from the father was unavailable. Functional studies of the variant and studies of patient cells were not performed. The patient was part of a larger cohort of 500 patients with epileptic encephalopathies who underwent targeted sequencing of candidate genes.
In a 3.5-year-old boy (patient 1464.524) with DEE54, Hamdan et al. (2014) identified a de novo heterozygous nonsense mutation in the HNRNPU gene (Q171X; 602869.0002). The mutation was not found in the Exome Variant Server database; functional studies of the variant and studies of patient cells were not performed. The patient was part of a cohort of 41 child-parent trios, in which the child had intellectual disability, who underwent exome sequencing.
In a girl (patient 2012D06376) with DEE54, de Kovel et al. (2016) identified a de novo frameshift mutation in the HNRNPU gene (602869.0003). The mutation was found by sequencing candidate genes for epileptic encephalopathy in 359 patients and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in nonsense-mediated mRNA decay. The patient was part of a larger cohort of 500 patients with epileptic encephalopathies who underwent targeted sequencing of candidate genes.
In an 11-year-old girl (trio hv) with DEE54, the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) identified a de novo heterozygous small insertion/deletion in a splice acceptor site of the HNRNPU gene, predicted to result in a modified protein. The patient was part of a larger cohort of 264 probands with epileptic encephalopathy who underwent exome sequencing. The patient had previously been reported by Need et al. (2012) as also carrying a de novo heterozygous mutation in the SMAD1 gene (601595). Functional studies of the variants and studies of patient cells were not performed.
Zhao et al. (2009) analyzed a mouse preaxial polydactyly (see 174500) model with a T-to-A point mutation in a conserved locus about 1 Mb upstream of the Shh (600725) coding region. A core element of mutation (CEM) with putative enhancer activity was identified by promoter activity assay and shown to contain a matrix attachment region. HnRNPU preferentially bound to the mutant but not the wildtype CEM. HnRNPU also bound to the 5-prime UTR of the Shh gene, which was not located in the nuclear matrix in wildtype embryonic cells. The authors proposed that the 5-prime UTR of Shh was pulled into the nuclear matrix by HnRNPU when the CEM was mutated, and consequently affected Shh expression. Therefore, distant cis-elements may modulate gene expression by altering the affinity of HNRNPU for certain mediator proteins and nuclear relocation.
In a 33-year-old man (patient T162) with developmental and epileptic encephalopathy-54 (DEE54; 617391), Carvill et al. (2013) identified a heterozygous mutation in the HNRNPU gene, resulting in an tyr805-to-ter (Y805X) substitution. The mutation was not present in the mother; DNA from the father was unavailable. Functional studies of the variant and studies of patient cells were not performed. The patient was part of a larger cohort of 500 patients with epileptic encephalopathies who underwent targeted sequencing of candidate genes. He had delayed development from early infancy and onset of various types of seizures at 2 years of age.
In a 3.5-year-old boy (patient 1464.524) with developmental and epileptic encephalopathy-54 (DEE54; 617391), Hamdan et al. (2014) identified a de novo heterozygous c.511C-T transition (c.511C-T, NM_031844.2) in the HNRNPU gene, resulting in a gln171-to-ter (Q171X) substitution. The mutation was not found in the Exome Variant Server database. The patient was part of a cohort of 41 child-parent trios, in which the child had intellectual disability, who underwent exome sequencing. Clinical details were sparse, but the child was noted to have severe intellectual disability, autistic features, and seizures. He was hypotonic and was unable to speak or walk. He had borderline microcephaly; brain imaging showed enlarged ventricles and myelination delay.
In a girl (patient 2012D06376) with developmental and epileptic encephalopathy-54 (DEE54; 617391), de Kovel et al. (2016) identified a de novo heterozygous 1-bp insertion (c.1810_1811insT, NM_031844.2) in the HNRNPU gene, resulting in a frameshift and premature termination (Val604fsTer24). The mutation, which was found by sequencing candidate genes for epileptic encephalopathy in 359 patients and confirmed by Sanger sequencing, was not found in the dbSNP (build 144), Exome Sequencing Project (May 2015), or ExAC database (June 2015). Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in nonsense-mediated mRNA decay. The patient was part of a larger cohort of 500 patients with epileptic encephalopathies who underwent targeted sequencing of candidate genes. She presented with developmental delay and febrile seizures at 8 months of age.
Carvill, G. L., Heavin, S. B., Yendle, S. C., McMahon, J. M., O'Roak, B. J., Cook, J., Khan, A., Dorschner, M. O., Weaver, M., Calvert, S., Malone, S., Wallace, G., and 22 others. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nature Genet. 45: 825-830, 2013. [PubMed: 23708187] [Full Text: https://doi.org/10.1038/ng.2646]
de Kovel, C. G. F., Brilstra, E. H., van Kempen, M. J. A., van't Slot, R., Nijman, I. J., Afawi, Z., De Jonghe, P., Djemie, T., Guerrini, R., Hardies, K., Helbig, I., Hendrickx, R., and 13 others. Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients. Molec. Genet. Genomic Med. 4: 568-580, 2016. [PubMed: 27652284] [Full Text: https://doi.org/10.1002/mgg3.235]
Epi4K Consortium and Epilepsy Phenome/Genome Project. De novo mutations in epileptic encephalopathies. Nature 501: 217-221, 2013. [PubMed: 23934111] [Full Text: https://doi.org/10.1038/nature12439]
Fackelmayer, F. O., Richter, A. hnRNP-U/SAF-A is encoded by two differentially polyadenylated mRNAs in human cells. Biochim. Biophys. Acta 1217: 232-234, 1994. [PubMed: 7509195] [Full Text: https://doi.org/10.1016/0167-4781(94)90044-2]
Hamdan, F. F., Srour, M., Capo-Chichi, J.-M., Daoud, H., Nassif, C., Patry, L., Massicotte, C., Ambalavanan, A., Spiegelman, D., Diallo, O., Henrion, E., Dionne-Laporte, A., Fougerat, A., Pshezhetsky, A. V., Venkateswaran, S., Rouleau, G. A., Michaud, J. L. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 10: e1004772, 2014. Note: Electronic Article. [PubMed: 25356899] [Full Text: https://doi.org/10.1371/journal.pgen.1004772]
Kiledjian, M., Dreyfuss, G. Primary structure and binding activity of the hnRNP U protein: binding RNA through RGG box. EMBO J. 11: 2655-2664, 1992. [PubMed: 1628625] [Full Text: https://doi.org/10.1002/j.1460-2075.1992.tb05331.x]
Need, A. C., Shashi, V., Hitomi, Y., Schoch, K., Shianna, K. V., McDonald, M. T., Meisler, M. H., Goldstein, D. B. Clinical application of exome sequencing in undiagnosed genetic conditions. J. Med. Genet. 49: 353-361, 2012. [PubMed: 22581936] [Full Text: https://doi.org/10.1136/jmedgenet-2012-100819]
Valente, S. T., Goff, S. P. Inhibition of HIV-1 gene expression by a fragment of hnRNP U. Molec. Cell 23: 597-605, 2006. [PubMed: 16916646] [Full Text: https://doi.org/10.1016/j.molcel.2006.07.021]
Zhao, J., Ding, J., Li, Y., Ren, K., Sha, J., Zhu, M., Gao, X. HnRNP U mediates the long-range regulation of Shh expression during limb development. Hum. Molec. Genet. 18: 3090-3097, 2009. [PubMed: 19477957] [Full Text: https://doi.org/10.1093/hmg/ddp250]