Alternative titles; symbols
HGNC Approved Gene Symbol: RNH1
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38): 11:494,515-507,242 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.5 | {Encephalopathy, acute, infection-induced, susceptibility to, 12} | 620461 | Autosomal recessive | 3 |
RNH1 belongs to a family of proteinaceous cytoplasmic RNase inhibitors found in many tissues that bind to both intracellular and extracellular RNases. In addition to inhibiting intracellular RNases, RNH1 may have a role in the regulation of angiogenin (ANG; 105850) (summary by Lee et al., 1988). RNH1 may also play a role in several different cellular pathways, including protein translation, regulation of the inflammasome, and scavenging of reactive oxygen species (summary by Hedberg-Oldfors et al., 2023).
Lee et al. (1988) determined the primary structure of PRI from the cDNA. The mature protein encodes a 460-amino acid polypeptide with a molecular mass of 49.8 kD. The amino acid sequence contains 7 direct internal repeat units, each 57 amino acids in length. These repeat units comprise 87% of the molecule. The average degree of identity between any 2 is 39%.
By cell fractionation and immunohistochemical analysis of human HeLa and HCT cells, Furia et al. (2011) found that RNH1 localized to mitochondria and nucleus, in addition to cytoplasm. RNH1 copurified with proteins of the mitochondrial matrix and inner membrane.
The RNH1 gene contains 11 exons (Hedberg-Oldfors et al., 2023).
Monti and D'Alessio (2004) found that knockdown of CRI via small interfering RNA (siRNA) made HeLa cells more sensitive to cytotoxic RNases, such as bovine seminal RNase and human pancreatic RNase (RNASE1; 180440). Knockdown of CRI did not render benign RNases cytotoxic.
Because of its high cysteine content (32 residues), Monti et al. (2007) hypothesized that CRI might contribute to cellular redox homeostasis. Knockdown of CRI via siRNA lowered the content of reduced glutathione and other small thiol compounds in HeLa cells and human umbilical vein endothelial cells. Knockdown of CRI also increased DNA damage and cell sensitivity to oxidative insult. Monti et al. (2007) found that reducing agents inhibited binding of CRI to immobilized RNase A.
PTEN (601728) is a lipid phosphatase that regulates cell signaling via phosphatidylinositols and functions as a tumor suppressor. Kim et al. (2011) presented evidence that PTEN regulates RNH1. Tandem affinity purification, followed by mass spectrometric analysis, identified RNH1 as a protein that interacted with PTEN in HEK293 cells. Kim et al. (2011) also found that RNH1 accelerated nuclear Drosha (RNASEN; 608828)-dependent processing of the microRNA-21 (MIR21; 611020) primary transcript (pri-MIR21) to the precursor stem-loop structure (pre-MIR21). RNH1 interacted directly with Drosha and appeared to interact with pri-MIR21. Addition of a nuclear localization signal to the RNH1 N terminus accelerated pri-MIR21 processing. Interaction of PTEN with RNH1 prevented interaction of RNH1 with Drosha and reduced pri-MIR21 processing in vitro and in HEK293 cells. Kim et al. (2011) concluded that PTEN tumor suppressor activity may, in part, be due to inhibited processing of MIR21, which can function as an oncogene.
Zhao et al. (2013) found that Rnh1 promoted differentiation and myelination of cultured primary rat oligodendrocytes. Rnh1 affected oligodendrocyte differentiation through RhoA (165390)-Rock (see 601702) signaling and elevated expression and phosphorylation of Fyn (137025).
By study of human-rodent somatic cell hybrids and by in situ hybridization, Weremowicz et al. (1990) mapped the PRI gene to 11p15. The localization was further refined to 11p15.5, distal to the IGF2 gene, by in situ hybridization to metaphase chromosomes from a cell line with a well-characterized translocation involving a breakpoint between IGF2 (147470) and HRAS (190020). Zneimer et al. (1990) localized the RNH gene to 11p15.5 by in situ hybridization.
In 2 sibs, born of consanguineous parents of Somali origin, with infection-induced acute encephalitis-12 (IIAE12; 620461), Hedberg-Oldfors et al. (2023) identified a homozygous splice site mutation in the RNH1 gene (173320.0001). The mutation, which was found by a combination of whole-exome and whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in public databases, including dbSNP (build 151), ExAC, Exome Sequencing Project, 1000 Genomes Project, and gnomAD. Western blot analysis of patient muscle tissue showed total absence of the RNH1 protein, consistent with a loss-of-function effect. Patient-derived fibroblasts showed increased sensitivity and increased apoptosis in response to RNase exposure, which was reversed by expression of wildtype RNH1. Noting that RNH1 has been shown to regulate inflammation, the authors hypothesized that the infection-induced deterioration in the patients may have resulted from lack of RNH1-mediated control of inflammasome activation.
In 8 children from 4 unrelated families with IIAE12, Shashi et al. (2023) identified homozygous or compound heterozygous mutations in the RNH1 gene (173320.0002-173320.0007). The patients were ascertained through the GeneMatcher program after exome or genome sequencing identified the mutations. The mutations were confirmed by Sanger sequencing and segregated with the disorder in the families; family 3 showed incomplete penetrance, as 2 unaffected family members also had biallelic mutations. There were 4 missense mutations, 1 nonsense, and 1 frameshift. All but 1 of the mutations affected highly conserved residues in LLR domains. Fibroblasts derived from patients in families 1 and 2 showed nearly undetectable RNH1 protein levels, suggesting a loss of function. Functional studies of the mutations were not performed.
Hedberg-Oldfors et al. (2023) noted that homozygous knockout of Rnh1 in mice is embryonic lethal and associated with anemia.
In 2 sibs, born of consanguineous parents of Somali origin, with infection-induced acute encephalitis-12 (IIAE12; 620461), Hedberg-Oldfors et al. (2023) identified a homozygous A-to-C transversion in intron 6 of the RNH1 gene (c.615-2A-C, NM_203387.3), predicted to result in a splicing defect. The mutation, which was found by a combination of whole-exome and whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in public databases, including dbSNP (build 151), ExAC, Exome Sequencing Project, 1000 Genomes Project, and gnomAD. Analysis of patient muscle tissue showed a mutant transcript lacking exon 7, which is predicted to result in an in-frame deletion of 57 amino acids (Leu206_Trp262del). Western blot analysis of patient muscle tissue showed total absence of the RNH1 protein, consistent with a loss-of-function effect. Patient-derived fibroblasts showed increased sensitivity and increased apoptosis in response to RNase exposure, which was reversed by expression of wildtype RNH1. In addition to IIAE12, these patients had congenital cataracts, hypotonia, and global developmental delay. One sib died at 8 months of age and the other had persistent neurologic deficits.
In 2 sibs, born of unrelated parents (family 1), with infection-induced acute encephalitis-12 (IIAE12; 620461), Shashi et al. (2023) identified compound heterozygous missense mutations in the RNH1 gene: a c.626G-A transition (c.626G-A, NM_203387.3) in exon 2, resulting in a cys209-to-tyr (C209Y) substitution, and a c.279G-T transversion in exon 5, resulting in a gln93-to-his (Q93H; 173320.0003) substitution. Both mutations affected conserved residues in LRR domains. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. C209Y was found in the heterozygous state only in 14 of 278,902 alleles in gnomAD, whereas Q93H was not present in gnomAD. Patient fibroblasts showed nearly undetectable RNH1 protein levels, suggesting a loss of protein function. One sib died of the disease at 3 years of age, whereas the other showed normal neurodevelopment at 10 years of age.
For discussion of the c.279G-T transversion (c.279G-T, NM_203387.3) in the RNH1 gene, resulting in a gln93-to-his (Q93H; 173320.0003) substitution, that was found in compound heterozygous state in 2 sibs with infection-induced acute encephalitis-12 (IIAE12; 620461) by Shashi et al. (2023), see 173320.0002.
In 2 brothers, born of consanguineous Guatemalan parents (family 2), with infection-induced acute encephalitis-12 (IIAE12; 620461), Shashi et al. (2023) identified a homozygous c.887T-C transition (c.887T-C, NM_203387.3) in exon 8 of the RNH1 gene, resulting in a leu296-to-pro (L296P) substitution at a conserved residue in an LRR domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Patient fibroblasts showed nearly undetectable RNH1 protein levels, suggesting a loss of protein function. One sib died in infancy and the other had profound neurologic deficits at age 5.
In 2 sibs (family 3) with susceptibility to infection-induced acute encephalitis-12 (IIAE12; 620461), Shashi et al. (2023) identified compound heterozygous mutations in the RNH1 gene: a c.1117C-T transition (c.1117C-T, NM_203387.3) in exon 9, resulting in an arg373-to-trp (R373W) substitution, and a c.40G-T transversion in exon 3, resulting in a glu14-to-ter (E14X) substitution (173320.0006). R373W affects a conserved residue in 1 of the C-terminal LRR domains and E14X is in the N-terminal region before the LRR domains. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Of note, these 2 mutations were also identified in 2 unaffected sibs (aged 7 and 24 years), suggesting incomplete penetrance. E14X was found once in the heterozygous state in gnomAD (1 of 235,042 alleles) and R373W was found in 9 of 281,378 alleles, only in the heterozygous state. Two sibs from another family (family 4) with the disorder were compound heterozygous for R373W and a del/ins mutation in exon 7 (c.682_685delins14; 173320.0007), predicted to result in a frameshift and premature termination (Ser228LeufsTer17); the latter mutation was not found in gnomAD. The mutations segregated with the disorder in family 4. Functional studies of the variants and studies of patient cells were not performed. One sib in family 3 died at age 2, whereas the other showed normal neurologic development at age 6. Both sibs in family 4 had profound neurologic and intellectual disabilities at 16 and 22 years of age.
For discussion of the c.40G-T transversion (c.40G-T, NM_203387.3) in the RNH1 gene, resulting in a glu14-to-ter (E14X) substitution, that was found in compound heterozygous state in 2 sibs with infection-induced acute encephalitis-12 (IIAE12; 620461) by Shashi et al. (2023), see 173320.0005.
For discussion of the del/ins mutation (c.682_685delinsCTGGGCCTTGGGCA, NM_203387.3) in the RNH1 gene, predicted to result in a frameshift and premature termination (Ser228LeufsTer17), that was found in compound heterozygous state in 2 sibs with infection-induced acute encephalitis-12 (IIAE12; 620461) by Shashi et al. (2023), see 173320.0005.
Furia, A., Moscato, M., Cali, G., Pizzo, E., Confalone, E., Amoroso, M. R., Esposito, F., Nitsch, L., D'Alessio, G. The ribonuclease angiogenin inhibitor is also present in mitochondria and nuclei. FEBS Lett. 585: 613-617, 2011. [PubMed: 21276451] [Full Text: https://doi.org/10.1016/j.febslet.2011.01.034]
Hedberg-Oldfors, C., Mitra, S., Molinaro, A., Visuttijai, K., Fogelstrand, L., Oldfors, A., Sterky, F. H., Darin, N. Ribonuclease inhibitor 1 (RNH1) deficiency cause congenital cataracts and global developmental delay with infection-induced psychomotor regression and anemia. Europ. J. Hum. Genet. 31: 887-894, 2023. [PubMed: 36935417] [Full Text: https://doi.org/10.1038/s41431-023-01327-7]
Kim, Y.-J., Park, S.-J., Choi, E. Y., Kim, S., Kwak, H. J., Yoo, B. C., Yoo, H., Lee, S.-H., Kim, D., Park, J. B., Kim, J. H. PTEN modulates miR-21 processing via RNA-regulatory protein RNH1. PLoS One 6: e28308, 2011. Note: Electronic Article. [PubMed: 22162762] [Full Text: https://doi.org/10.1371/journal.pone.0028308]
Lee, F. S., Fox, E. A., Zhou, H.-M., Strydom, D. J., Vallee, B. L. Primary structure of human placental ribonuclease inhibitor. Biochemistry 27: 8545-8553, 1988. Note: Erratum: Biochemistry 28: 7138 only, 1989. [PubMed: 3219362] [Full Text: https://doi.org/10.1021/bi00423a007]
Monti, D. M., D'Alessio, G. Cytosolic RNase inhibitor only affects RNases with intrinsic cytotoxicity. J. Biol. Chem. 279: 39195-39198, 2004. [PubMed: 15277533] [Full Text: https://doi.org/10.1074/jbc.C400311200]
Monti, D. M., Montesano Gesualdi, N., Matousek, J., Esposito, F., D'Alessio, G. The cytosolic ribonuclease inhibitor contributes to intracellular redox homeostasis. FEBS Lett. 581: 930-934, 2007. [PubMed: 17292889] [Full Text: https://doi.org/10.1016/j.febslet.2007.01.072]
Shashi, V., Schoch, K., Ganetzky, R., Kranz, P. G., Sondheimer, N., Markert, M. L., Cope, H., Sadeghpour, A., Roehrs, P., Arbogast, T., Muraresku, C., Undiagnosed Diseases Network, and 16 others. Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy. Genet. Med. 25: 100897, 2023. [PubMed: 37191094] [Full Text: https://doi.org/10.1016/j.gim.2023.100897]
Weremowicz, S., Fox, E. A., Morton, C. C., Vallee, B. L. The placental ribonuclease inhibitor (RNH) gene is located on chromosome subband 11p15.5. Genomics 8: 717-721, 1990. [PubMed: 2276743] [Full Text: https://doi.org/10.1016/0888-7543(90)90260-2]
Zhao, C. F., Liu, Y., Que, H. P., Yang, S. G., Liu, T., Liu, Z. Q., Hui, H. D., Liu, S. Rnh1 promotes differentiation and myelination via RhoA in oligodendrocytes. Cell Tissue Res. 353: 381-389, 2013. [PubMed: 23624614] [Full Text: https://doi.org/10.1007/s00441-013-1625-7]
Zneimer, S. M., Crawford, D., Schneider, N. R., Beutler, B. Mapping of the human ribonuclease inhibitor gene (RNH) to chromosome 11p15 by in situ hybridization. Genomics 8: 175-178, 1990. [PubMed: 2081593] [Full Text: https://doi.org/10.1016/0888-7543(90)90242-m]