Alternative titles; symbols
HGNC Approved Gene Symbol: PRMT7
Cytogenetic location: 16q22.1 Genomic coordinates (GRCh38): 16:68,311,019-68,360,870 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q22.1 | Short stature, brachydactyly, intellectual developmental disability, and seizures | 617157 | Autosomal recessive | 3 |
Arginine methylation is an apparently irreversible protein modification catalyzed by arginine methyltransferases, such as PMT7, using S-adenosylmethionine (AdoMet) as the methyl donor. Arginine methylation is implicated in signal transduction, RNA transport, and RNA splicing (Miranda et al., 2004).
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2001) cloned PRMT7, which they designated KIAA1933. The 5-prime UTR of the cDNA contains 3 SINEs. RT-PCR ELISA detected moderate expression in adult brain and lung. Expression was weak in most other adult and fetal tissues and specific brain regions examined.
By searching databases for sequences similar to PRMTs, Miranda et al. (2004) identified PRMT7. The deduced 692-amino acid protein has 2 methyltransferase domains, each containing a putative AdoMet-binding motif. The N-terminal methyltransferase domain is most similar to the catalytic core of PRMT5 (604045), and the C-terminal domain is most similar to PRMT1 (602950). Database analysis revealed PRMT7 homologs in several animal and plant species, but not in yeast or prokaryotes.
Lee et al. (2005) identified 3 PRMT7 splice variants by database analysis. Transfection of COS cells with the longest variant resulted in localization of epitope-tagged PRMT7 to the nucleus and cytoplasm.
Miranda et al. (2004) found that recombinant PRMT7 methylated a synthetic peptide containing the methyltransferase target sequence of fibrillarin (FBL; 134795), but it could not methylate a larger glycine/arginine-rich (GAR) fragment of fibrillarin or other common PRMT substrates. Crosslinking experiments showed that the N-terminal methyltransferase domain of PRMT7 interacted with AdoMet, but the C-terminal domain did not.
Lee et al. (2005) found that recombinant PRMT7 and PRMT7 immunopurified from transfected HeLa cells methylated histone H2A (see 601772), histone H4 (see 602822), MBP (159430), the GAR fragment of fibrillarin, spliceosomal protein SMB (182282), and an isolated GRG tripeptide. PRMT7 produced predominantly monomethylarginine and symmetric dimethylarginine modifications, indicating that PRMT7 is a type II PRMT.
By genomic sequence analysis, Miranda et al. (2004) mapped the PRMT7 gene to chromosome 16q22.1.
In 6 females from 3 unrelated families with short stature, brachydactyly, impaired intellectual development, and seizures (SBIDDS; 617157), Akawi et al. (2015) identified compound heterozygous mutations in the PRMT7 gene (610087.0001-610087.0005). The mutations, which were found by exome sequencing, segregated with the disorder in the families. The patients were part of a large study of 4,125 families with a variety of severe developmental disorders who underwent exome analysis. The mutations were predicted to result in a loss of function, but functional studies of the variants and studies of patient cells were not performed.
In a boy, born of consanguineous parents of Afghan descent, with SBIDDS, Kernohan et al. (2017) identified a homozygous 15,309-bp deletion encompassing the transcriptional start site of the PRMT7 gene (610087.0006). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Western blot analysis of patient-derived cells showed complete absence of the PRMT7 protein and transcript, consistent with a loss of function. Analysis of patient cells showed decreased arginine methylation of target proteins, including certain core histone proteins such as H2B (see 609904) and H4. Patient cells also showed abnormal expression of genes within the Wnt signaling pathway. Parental cells showed decreased methylation levels compared to controls, consistent with haploinsufficiency.
In 2 sibs with SBIDDS, Birnbaum et al. (2019) identified a homozygous frameshift mutation in the PRMT7 gene (610087.0007). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. No functional studies were performed.
Akawi et al. (2015) found that Prm7-null mice had decreased viability (45% survival by day P14). Surviving mice showed increased fat mass, reduced length, limb bone anomalies, including shortened fifth metatarsals, and decreased bone mineral density and content. Some of the changes were more significant in females.
In 2 sisters (family 1) with short stature, brachydactyly, impaired intellectual development, and seizures (SBIDDS; 617157), Akawi et al. (2015) identified compound heterozygous mutations in the PRMT7 gene: a c.1276-1G-A transition (c.1276-1G-A, NM_019023.2), predicted to result in a splice site defect and a loss of function, and a c.1480T-C transition, resulting in a trp494-to-arg (W494R; 610087.0002) substitution. Functional studies of the variants and studies of patient cells were not performed.
For discussion of the c.1480T-C transition (c.1480T-C, NM_019023.2) in the PRMT7 gene, resulting in a trp494-to-arg (W494R) substitution, that was found in compound heterozygous state in 2 sisters with short stature, brachydactyly, impaired intellectual development, and seizures (SBIDDS; 617157) by Akawi et al. (2015), see 610087.0001.
In 4 females from 2 unrelated families (families 2 and 3) with short stature, brachydactyly, impaired intellectual development, and seizures (SBIDDS; 617157), Akawi et al. (2015) identified compound heterozygous mutations in the PRMT7 gene. All patients carried a c.95G-C transversion (c.95G-C, NM_019023.2) at the last base of the first coding exon, which could either result in a splice site defect or an arg32-to-thr (R32T) substitution, on 1 allele. The patient from family 2 carried a c.1159A-G transition, resulting in an arg387-to-gly (R387G; 610087.0004) on the other allele, and the 3 sisters from family 3 carried a c.1056-1G-T transversion (610087.0005), predicted to result in a splice site defect and loss of function on the other allele. Functional studies of the variants and studies of patient cells were not performed.
For discussion of the c.1159A-G transition (c.1159A-G, NM_019023.2) in the PRMT7 gene, resulting in an arg387-to-gly (R387G) substitution that was found in compound heterozygous state in a woman with short stature, brachydactyly, impaired intellectual development, and seizures (SBIDDS; 617157) by Akawi et al. (2015), see 610087.0003.
For discussion of the c.1056-1G-T transversion (c.1056-1G-T, NM_019023.2) in the PRMT7 gene, predicted to result in a splice site defect and loss of function, that was found in compound heterozygous state in 3 sisters with short stature, brachydactyly, impaired intellectual development, and seizures (SBIDDS; 617157) by Akawi et al. (2015), see 610087.0003.
In a boy, born of consanguineous parents of Afghan descent, with short stature, brachydactyly, impaired intellectual development, and seizures (SBIDDS; 617157), Kernohan et al. (2017) identified a homozygous 15,309-bp deletion (chr16.68,345,747-68,361,056, GRCh37) encompassing the transcriptional start site of the PRMT7 gene. The mutation, which was found by whole-exome sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases and 2,000 in-house control exomes. PCR analysis confirmed segregation of the mutation with the disorder in the family. Western blot analysis of patient-derived cells showed complete absence of the PRMT7 protein and transcript, consistent with a loss of function. Analysis of patient cells showed decreased arginine methylation of target proteins, including certain core histone proteins such as H2B and H4. Patient cells also showed abnormal expression of genes within the Wnt signaling pathway. Parental cells showed decreased methylation levels compared to controls, consistent with haploinsufficiency.
In 2 sibs with short stature, brachydactyly, impaired intellectual development, and seizures (SBIDDS; 617157), Birnbaum et al. (2019) identified a homozygous 2-bp deletion (c.1074_1075delAG, NM_001290018.1) in the PRMT7 gene, predicting a frameshift and a premature termination codon (Arg358fsTer9). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was predicted to abolish the C-terminal domain of the protein, suggesting loss of function. Functional studies were not performed.
Akawi, N., McRae, J., Ansari, M., Balasubramanian, M., Blyth, M., Brady, A. F., Clayton, S., Cole, T., Deshpande, C., Fitzgerald, T. W., Foulds, N., Francis, R., and 30 others. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families. Nature Genet. 47: 1363-1369, 2015. [PubMed: 26437029] [Full Text: https://doi.org/10.1038/ng.3410]
Birnbaum, R., Yosha-Orpaz, N., Yanoov-Sharav, M., Kidron, D., Gur, H., Yosovich, K., Lerman-Sagie, T., Malinger, G. Prenatal and postnatal presentation of PRMT7 related syndrome: expanding the phenotypic manifestations. Am. J. Med. Genet. 179A: 78-84, 2019. [PubMed: 30513135] [Full Text: https://doi.org/10.1002/ajmg.a.6]
Kernohan, K. D., McBride, A., Xi, Y., Martin, N., Schwartzentruber, J., Dyment, D. A., Majewski, J., Blaser, S. Care4Rare Canada Consortium, Boycott, K. M., Chitayat, D. Loss of the arginine methyltranserase (sic) PRMT7 causes syndromic intellectual disability with microcephaly and brachydactyly. Clin. Genet. 91: 708-716, 2017. [PubMed: 27718516] [Full Text: https://doi.org/10.1111/cge.12884]
Lee, J.-H., Cook, J. R., Yang, Z.-H., Mirochnitchenko, O., Gunderson, S. I., Felix, A. M., Herth, N., Hoffmann, R., Pestka, S. PRMT7, a new protein arginine methyltransferase that synthesizes symmetric dimethylarginine. J. Biol. Chem. 280: 3656-3664, 2005. [PubMed: 15494416] [Full Text: https://doi.org/10.1074/jbc.M405295200]
Miranda, T. B., Miranda, M., Frankel, A., Clarke, S. PRMT7 is a member of the protein arginine methyltransferase family with a distinct substrate specificity. J. Biol. Chem. 279: 22902-22907, 2004. [PubMed: 15044439] [Full Text: https://doi.org/10.1074/jbc.M312904200]
Nagase, T., Kikuno, R., Ohara, O. Prediction of the coding sequences of unidentified human genes. XXI. The complete sequences of 60 new cDNA clones from brain which code for large proteins. DNA Res. 8: 179-187, 2001. [PubMed: 11572484] [Full Text: https://doi.org/10.1093/dnares/8.4.179]