Alternative titles; symbols
HGNC Approved Gene Symbol: HNRNPH2
Cytogenetic location: Xq22.1 Genomic coordinates (GRCh38) : X:101,408,222-101,414,133 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq22.1 | Intellectual developmental disorder, X-linked syndromic, Bain type | 300986 | X-linked dominant | 3 |
The HNRNPH2 gene encodes a member of the heterogeneous nuclear ribonucleoprotein (hnRNPs) family. This family constitutes a set of polypeptides that bind heterogeneous nuclear RNA (hnRNA), the transcripts produced by RNA polymerase II (see 180660). Proteins in the HNRNP family localize to the nucleus and shuttle pre-mRNA transcripts between the nucleus and cytoplasm for processing and transport. More than 20 such proteins have been described and designated with letters from A to U (summary by Honore et al., 1995).
By molecular cDNA cloning, 2-dimensional gel immunoblotting, and amino acid microsequencing, Honore et al. (1995) identified 3 sequence-unique and distinct proteins that constitute a subfamily of ubiquitously expressed hnRNPs. The identity between hnRNPs H (HNRNPH1; 601035) and H-prime (HNRNPH2) is 96%, between H and F (HNRNPF; 601037) is 78%, and between H-prime and F is 75%.
Grammatikakis et al. (2016) noted that, in rodents, alternative splicing produces a short Trf2 (TERF2; 602027) variant, Trf2s, that includes only part of exon 7 and is involved in derepression of neuronal genes. Using a proteomic screen of rat cerebellar extracts, Grammatikakis et al. (2016) found that the RNA-binding proteins Hnrnph1 and Hnrnph2 interacted with exon 7 of Trf2 pre-mRNA. The HNRNPH proteins inhibited use of the 5-prime alternative splice site in exon 7, promoting inclusion of exon 7 and thereby increasing the relative levels of full-length Trf2 and lowering Trf2s abundance. HNRNPH protein levels decreased during neuronal differentiation, whereas Trf2s levels increased. CRISPR-mediated deletion of Hnrnph2 accelerated neuronal differentiation. Grammatikakis et al. (2016) concluded that HNRNPH1 and HNRNPH2 repress neuronal differentiation, at least in part, by inhibiting alternative splicing of TRF2.
By fluorescence in situ hybridization (FISH), Honore et al. (1995) mapped the HNRPH2 gene to either 6q25.3-q26 or Xq22 (or both). Vorechovsky et al. (1994) isolated a homologous cDNA by direct cDNA selection using YACs from the region Xq21.3-q22. The FISH mapping by Honore et al. (1995) placed the signal in the distal part of that segment. However, a specific signal was also observed at 6q25.3-q26, indicating the presence of either 2 genes or a pseudogene. Since the signal was stronger on chromosome 6, Honore et al. (1995) suggested that this is a functional gene.
In 5 unrelated female patients with the Bain type of X-linked syndromic intellectual developmental disorder (MRXSB; 300986), Bain et al. (2016) identified 2 different de novo heterozygous missense mutations in the HNRNPH2 gene: 3 patients carried the same variant (R206W; 300610.0001), 1 carried a different mutation at the same residue (R206Q; 300610.0002), and 1 carried a mutation that was 3 amino acids away (P209L; 300610.0003). All mutations affected conserved residues in the nuclear localization sequence. The patients were from a large cohort of 2,030 females and 2,486 males with developmental delay and/or intellectual disability who underwent whole-exome sequencing. Bain et al. (2016) noted that a sixth female patient with the R206W mutation and a similar phenotype was identified by another laboratory. Functional studies of the variants and studies of patient cells were not performed; however, Bain et al. (2016) noted that all mutations affected highly conserved residues in the nuclear localization sequence, and postulated a toxic gain-of-function effect. The authors suggested that these variants may be lethal in males.
In a boy with MRXSB, Harmsen et al. (2019) identified a hemizygous de novo missense mutation in the HNRNPH2 gene (R206Q; 300610.0002). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not present in his mother. The authors stated that this diagnosis should be considered in males with profound developmental delay, intellectual disability, and secondary microcephaly.
By whole-exome and Sanger sequencing in 2 boys with MRXSB, Jepsen et al. (2019) identified hemizygous mutations in the HNRNPH2 gene. The first boy had the previously identified R206W mutation (300610.0001) and the second boy had a novel R114W mutation (300610.0004). In the second boy, exome sequencing revealed 7% reference reads and 93% variant reads, suggesting low-level mosaicism for the reference allele. These findings provided further support that this condition is not embryonically lethal in males.
In a brother and sister, born to consanguineous Indian parents, with MRXSB, Somashekar et al. (2020) identified the previously reported R206Q mutation in the HNRNPH2 gene in hemizygous and heterozygous state, respectively. Both parents were found to have the wildtype allele. Identification of a pathogenic variant in HNRNPH2 in another male patient confirmed that this X-linked condition is compatible with postnatal survival in boys. The authors proposed that maternal germline mosaicism was the most likely explanation for the occurrence in sibs.
In 3 unrelated females with the Bain type of X-linked syndromic intellectual developmental disorder (MRXSB; 300986), Bain et al. (2016) identified a de novo heterozygous c.616C-T transition (c.616C-T, NM_019597.4) in the HNRNPH2 gene, resulting in an arg206-to-trp (R206W) substitution at a highly conserved residue in the nuclear localization sequence (NLS). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project database and was not found in the ExAC database. Bain et al. (2016) noted that a fourth female patient with the R206W mutation and a similar phenotype was identified by another laboratory. Functional studies of the variant and studies of patient cells were not performed, but Bain et al. (2016) postulated a toxic gain-of-function effect.
By whole-exome sequencing in a boy with MRXSB, Jepsen et al. (2019) identified the R206W mutation in the HNRNPH2 gene.
In a girl with the Bain type of X-linked syndromic intellectual developmental disorder (MRXSB; 300986), Bain et al. (2016) identified a de novo heterozygous c.617G-A transition (c.617G-A, NM_019597.4) in the HNRNPH2 gene, resulting in an arg206-to-gln (R206Q) substitution at a highly conserved residue in the nuclear localization sequence (NLS). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project database and was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed, but Bain et al. (2016) postulated a toxic gain-of-function effect.
By whole-exome and Sanger sequencing in a boy with MRXSB, Jepsen et al. (2019) identified de novo hemizygosity for the R206Q mutation in the HNRNPH2 gene. The mutation was not present in his mother.
In a brother and sister with MRXSB, who were born to consanguineous Indian parents, Somashekar et al. (2020) identified hemizygosity and heterozygosity for the R206Q mutation in the HNRNPH2 gene, respectively. Both parents were found to have the wildtype allele. The authors proposed that maternal germline mosaicism was the most likely explanation for occurrence in sibs.
In a girl with the Bain type of X-linked syndromic intellectual developmental disorder (MRXSB; 300986), Bain et al. (2016) identified a de novo heterozygous c.626C-T transition (c.616C-T, NM_019597.4) in the HNRNPH2 gene, resulting in a pro209-to-leu (P209L) substitution at a highly conserved residue in the nuclear localization sequence (NLS). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project database and was not found in the ExAC database. Functional studies of the variant and studies of patient cells were not performed, but Bain et al. (2016) postulated a toxic gain-of-function effect.
By whole-exome sequencing in a boy with the Bain type of X-linked syndromic intellectual developmental disorder (MRXSB; 300986), Jepsen et al. (2019) identified a hemizygous c.340C-T transition in the HNRNPH2 gene, resulting in an arg114-to-trp (R114W) substitution. Exome sequencing revealed 7% reference reads and 93% variant reads, suggesting low-level mosaicism for the reference allele. The finding was confirmed by Sanger sequencing.
Bain, J. M., Cho, M. T., Telegrafi, A., Wilson, A., Brooks, S., Botti, C., Gowans, G., Autullo, L. A., Krishnamurthy, V., Willing, M. C., Toler, T. L., Ben-Zev, B., Elpeleg, O., Shen, Y., Retterer, K., Monaghan, K. G., Chung, W. K. Variants in HNRNPH2 on the X chromosome are associated with a neurodevelopmental disorder in females. Am. J. Hum. Genet. 99: 728-734, 2016. [PubMed: 27545675] [Full Text: https://doi.org/10.1016/j.ajhg.2016.06.028]
Grammatikakis, I., Zhang, P., Panda, A. C., Kim, J., Maudsley, S., Abdelmohsen, K., Yang, X., Martindale, J. L., Motino, O., Hutchison, E. R., Mattson, M. P., Gorospe, M. Alternative splicing of neuronal differentiation factor TRF2 regulated by HNRNPH1/H2. Cell Rep. 15: 926-934, 2016. [PubMed: 27117401] [Full Text: https://doi.org/10.1016/j.celrep.2016.03.080]
Harmsen, S., Buchert, R., Mayatepek, E., Haack, T. B., Distelmaier, F. Bain type of X-linked syndromic mental retardation in boys. (Letter) Clin. Genet. 95: 734-735, 2019. [PubMed: 30887513] [Full Text: https://doi.org/10.1111/cge.13524]
Honore, B., Rasmussen, H. H., Vorum, H., Dejgaard, K., Liu, X., Gromov, P., Madsen, P., Gesser, B., Tommerup, N., Celis, J. E. Heterogeneous nuclear ribonucleoproteins H, H-prime, and F are members of a ubiquitously expressed subfamily of related but distinct proteins encoded by genes mapping to different chromosomes. J. Biol. Chem. 270: 28780-28789, 1995. [PubMed: 7499401] [Full Text: https://doi.org/10.1074/jbc.270.48.28780]
Jepsen, W. M., Ramsey, K., Szelinger, S., Llaci, L., Balak, C., Belnap, N., Bilagody, C., De Both, M., Gupta, R., Naymik, M., Pandey, R., Piras, I. S., Sanchez-Castillo, M., Rangasamy, S., Narayanan, V., Huentelman, M. J. Two additional males with X-linked, syndromic mental retardation carry de novo mutations in HNRNPH2. (Letter) Clin. Genet. 96: 183-185, 2019. [PubMed: 31236915] [Full Text: https://doi.org/10.1111/cge.13580]
Somashekar, P. H., Narayanan, D. L., Jagadeesh, S., Suresh, B., Vaishnavi, R. D., Bielas, S., Girisha, K. M., Shukla, A. Bain type of X-linked syndromic mental retardation in a male with a pathogenic variant in HNRNPH2. Am. J. Med. Genet. 182A: 183-188, 2020. [PubMed: 31670473] [Full Text: https://doi.org/10.1002/ajmg.a.61388]
Vorechovsky, I., Vetrie, D., Holland, J., Bentley, D. R., Thomas, K., Zhou, J.-N., Notarangelo, L. D., Plebani, A., Fontan, G., Ochs, H. D., Hammarstrom, L., Sideras, P., Smith, C. I. E. Isolation of cosmid and cDNA clones in the region surrounding the BTK gene at Xq21.3-q22. Genomics 21: 517-524, 1994. [PubMed: 7959728] [Full Text: https://doi.org/10.1006/geno.1994.1310]