Alternative titles; symbols
HGNC Approved Gene Symbol: PRR12
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:49,591,182-49,626,439 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.33 | Neuroocular syndrome | 619539 | Autosomal dominant | 3 |
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (1999) cloned PRR12, which they designated KIAA1205. The deduced protein contains 1,217 amino acids.
Cordova-Fletes et al. (2015) used total homogenates to analyze Prr12 expression in the mouse and rat brain. Immunoblot assays showed a 212-kD band that appeared to correspond to human PRR12 isoform 3, and showed strongest expression of that isoform at embryonic day 15 (E15) in both mouse and rat, compared to postnatal day 1 (P1) and adult mouse brain and compared to P1 in the rat. Using density gradient fractionation and Western blot, the authors analyzed subcellular localization in the mouse brain and observed that expression was confined to the nucleus in all tested stages (E15, P1, and adult). They noted that expression was much lower in the adult brain, suggesting an important role for PRR12 in early CNS development. Another approximately 150-kD band was observed in and outside of the nucleus, appearing in perisynapses, synaptosomes, and the postsynaptic density. The authors suggested that this smaller isoform might have a signaling role.
By radiation hybrid analysis, Nagase et al. (1999) mapped the PRR12 gene to chromosome 19. Hartz (2015) mapped the PRR12 gene to chromosome 19q13.33 based on an alignment of the PRR12 sequence (GenBank AB033031) with the genomic sequence (GRCh38).
Cordova-Fletes et al. (2015) reported an 11-year-old Mexican girl with intellectual disability and neuropsychiatric abnormalities (see NOC; 619539) who had a de novo balanced t(10;19)(q22.3;q13.33) translocation. Fine mapping of breakpoints revealed disruptions of the ZMIZ1 gene (607159) on chromosome 10 and the PRR12 gene on chromosome 19, resulting in gene fusions causing frameshifts predicted to result in premature termination codons. The authors suggested that the Coffin-Siris-like phenotype (see 135900) was likely due to ZMIZ1 alteration.
In 3 unrelated children with neuroocular syndrome (NOC1; 619539), Leduc et al. (2018) identified heterozygosity for de novo truncating mutations in the PRR12 gene (see, e.g., 616633.0001 and 616633.0002). The patients all exhibited intellectual disability, neuropsychiatric abnormalities, and iris anomalies. While all 3 mutations affected the longer PRR12 transcript, only 1 also affected the shorter transcript, suggesting that the longer of the 2 might be the functionally relevant transcript.
In 5 patients from 4 families with ocular anomalies with or without additional nonocular abnormalities, Reis et al. (2021) identified heterozygous truncating mutations in the PRR12 gene (see, e.g., 616633.0003). None of the variants were found in the gnomAD database. The authors noted that the ocular phenotypes were asymmetric in all affected individuals, and 1 patient exhibited only complex ocular anomalies.
Through international collaboration via GeneMatcher and Matchmaker Exchange, Chowdhury et al. (2021) identified 20 patients with neuroocular syndrome and heterozygous mutations in the PRR12 gene (see, e.g., 616633.0004-616633.0006), including 10 frameshift, 5 nonsense, 1 splice site, and 2 missense variants. In addition, 1 individual had a 3.352-Mb deletion at 19q13.33-13.41 involving 146 genes including PRR12. Sequencing of biologic parents, when possible, revealed that all PRR12 variants occurred de novo; none was found in the gnomAD database.
In a 4.75-year-old girl (patient 1) with neuroocular syndrome (NOC1; 619539), Leduc et al. (2018) identified heterozygosity for a c.1918G-T transversion (c.1918G-T, NM_020719) in exon 4 of the PRR12 gene, resulting in a glu640-to-ter (E640X) substitution. Neither parent carried the mutation, indicating that it arose de novo in the proband. The authors noted that this mutation affected only the longer transcript of the PRR12 gene.
In an 8-year-old boy (patient 2) with neuroocular syndrome (NOC1; 619539), Leduc et al. (2018) identified heterozygosity for a 4-bp deletion (c.4502_4505delTGCC, NM_020719) in exon 6 of the PRR12 gene, causing a frameshift predicted to result in a premature termination codon (Leu1501ArgfsTer146). Neither parent carried the mutation, indicating that it arose de novo in the proband. The authors noted that this mutation affected both the long and short transcripts of the PRR12 gene.
In a mother and daughter (family 1) with neuroocular syndrome (NOC1; 619539), Reis et al. (2021) identified heterozygosity for a splice site mutation (c.5624-2A-G, NM_020719.2) in intron 10 of the PRR12 gene, predicted to cause skipping of exon 11, resulting in a frameshift and premature termination (Asp1875GlyfsTer54). The mutation was not found in the mother's father or in the gnomAD database; DNA was unavailable from the mother's mother.
In a 10-year-old girl (patient 13) and an unrelated 15-month-old boy (patient 14) with neuroocular syndrome (NOC1; 619539), Chowdhury et al. (2021) identified heterozygosity for a 1-bp deletion (c.3273delC, NM_020719.3) in exon 4 of the PRR12 gene, causing a frameshift predicted to result in a premature termination codon (Lys1092ArgfsTer131). Segregation analysis revealed that the mutation arose de novo in both probands.
In a 5-month-old Filipino boy (patient 15) with neuroocular syndrome (NOC1; 619539), Chowdhury et al. (2021) identified heterozygosity for a c.3505C-T transition (c.3505C-T, NM_020719.3) in exon 4 of the PRR12 gene, resulting in an arg1169-to-trp (R1169W) substitution within the AT-hook domain. Segregation analysis revealed that the mutation arose de novo in the proband.
In a 15-year-old Italian boy (patient 20) with neuroocular syndrome (NOC1; 619539), Chowdhury et al. (2021) identified heterozygosity for a c.5909T-C transition (c.5909T-C, NM_020719.3) in exon 13 of the PRR12 gene, resulting in a leu1970-to-pro (L1970P) substitution. Segregation analysis revealed that the mutation arose de novo in the proband.
Chowdhury, F., Wang, L., Al-Raqad, M., Amor, D. J., Baxova, A., Bendova, S., Biamino, E., Brusco, A., Caluseriu, O., Cox, N. J., Froukh, T., Gunay-Aygun, M., and 32 others. Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities. Genet. Med. 23: 1234-1245, 2021. [PubMed: 33824499] [Full Text: https://doi.org/10.1038/s41436-021-01129-6]
Cordova-Fletes, C., Dominguez, M. G., Delint-Ramirez, I., Martinez-Rodriguez, H. G., Rivas-Estilla, A. M., Barros-Nunez, P., Ortiz-Lopez, R., Neira, V. A. A de novo t(10;19)(q22.3;q13.33) leads to ZMIZ1/PRR12 reciprocal fusion transcripts in a girl with intellectual disability and neuropsychiatric alterations. Neurogenetics 16: 287-298, 2015. [PubMed: 26163108] [Full Text: https://doi.org/10.1007/s10048-015-0452-2]
Hartz, P. A. Personal Communication. Baltimore, Md. 11/4/2015.
Leduc, M. S., Mcguire, M., Madan-Khetarpal, S., Ortiz, D., Hayflick, S., Keller, K., Eng, C. M., Yang, Y., Bi, W. De novo apparent loss-of-function mutations in PRR12 in three patients with intellectual disability and iris abnormalities. Hum. Genet. 137: 257-264, 2018. [PubMed: 29556724] [Full Text: https://doi.org/10.1007/s00439-018-1877-0]
Nagase, T., Ishikawa, K., Kikuno, R., Hirosawa, M., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6: 337-345, 1999. [PubMed: 10574462] [Full Text: https://doi.org/10.1093/dnares/6.5.337]
Reis, L. M., Costakos, D., Wheeler, P. G., Bardakjian, T., Schneider, A., Fung, S. S. M., University of Washington Center for Mendelian Genomics., Semina, E. V. Dominant variants in PRR12 result in unilateral or bilateral complex microphthalmia. Clin. Genet. 99: 437-442, 2021. [PubMed: 33314030] [Full Text: https://doi.org/10.1111/cge.13897]