Alternative titles; symbols
HGNC Approved Gene Symbol: MKRN3
Cytogenetic location: 15q11.2 Genomic coordinates (GRCh38) : 15:23,565,674-23,568,044 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q11.2 | Precocious puberty, central, 2 | 615346 | Autosomal dominant | 3 |
Jong et al. (1999) characterized 2 genes, termed ZNF127 (MKRN3) and ZNF127AS (603857), which are encoded in the complex imprinted locus on 15q11-q13. The ZNF127 gene encodes a 507-amino acid protein with a RING (C3HC4) zinc finger motif and multiple C3H zinc finger motifs, the former being closely related to a protein from variola major virus, the smallpox etiologic agent. These motifs predict ribonucleoprotein function for the ZNF127 polypeptide. Northern blot analysis revealed that the intronless ZNF127 gene is expressed ubiquitously as an approximately 3-kb transcript; however, the entire coding sequence and 5-prime CpG island overlap a second gene, ZNF127AS, which is transcribed from the antisense strand with a different transcript size and pattern of expression. Allele-specific analysis showed that the ZNF127 gene is expressed only from the paternal allele. Consistent with this expression pattern, in the brain, the ZNF127 5-prime CpG island is completely unmethylated on the paternal allele but methylated on the maternal allele. Analysis of adult testis, sperm, and fetal oocytes demonstrated a gametic methylation imprint with unmethylated paternal germ cells. Other work indicated that the ZNF127 gene is part of a coordinately regulated imprinted domain affected in Prader-Willi syndrome (PWS; 176270) patients with imprinting mutations (Nicholls et al., 1998). Therefore, ZNF127 and ZNF127AS are novel imprinted genes that may be associated with some of the clinical features of the polygenic Prader-Willi syndrome.
Jong et al. (1999) characterized the murine ZNF127 ortholog, termed Zfp127, which encodes a homologous putative zinc finger polypeptide. The mouse and human ZNF127 polypeptide sequences share similar structural motifs, including all 5 putative zinc finger motifs, and they have an overall identity of 69% at the amino acid level. Using RT-PCR across an in-frame hexamer tandem repeat and RNA from an interspecific F1 cross, Jong et al. (1999) showed that the Zfp127 gene is expressed only from the paternal allele in brain, heart, and kidney. Similarly, Zfp127 was expressed in differentiated cells derived from androgenetic embryonic stem cells and normal embryos but not those from parthogenetic embryonic stem cells. Jong et al. (1999) hypothesized that the gametic imprint may be set, at least in part, by the transcriptional activity of Zfp127 in pre- and postmeiotic male germ cells. They concluded that Zfp127 is a novel imprinted gene that may play a role in the imprinted phenotype of mouse models of PWS.
The hypothalamic arcuate nucleus is the site of expression of several genes known to be important for puberty, including Kiss1 (603286) and Tac2 (TAC3; 162330). Abreu et al. (2013) performed quantitative real-time PCR to assess Mkrn3 mRNA levels in the arcuate nucleus of mice, and observed in both male and female mice that levels were highest on postnatal days 10 and 12, began to decline on day 15, and reached a nadir by days 18 to 22, at which time Mkrn3 expression was 10 to 20% of the levels detected at 10 days. The timing of the decline in Mkrn3 expression correlated with the ages at which arcuate Kiss1 and Tac2 have been shown to increase, heralding the onset of puberty.
Abreu et al. (2013) performed whole-exome sequencing in 40 members of 15 families with central precocious puberty (CPPB2; 615346) and identified heterozygosity for 3 frameshift mutations and 1 missense mutation in the MKRN3 gene (603856.0001-603856.0004) in affected individuals from 5 of the families. Sanger sequencing confirmed the mutations, and there was complete cosegregation with the phenotype in each of the families. All affected family members inherited their mutations from their fathers, consistent with a paternally expressed imprinted gene; the 1 heterozygous carrier known to have inherited his mutation from his mother was unaffected.
Perry et al. (2014) performed a metaanalysis using genomewide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, and found robust evidence (p less than 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with 3 loci (DLK1, 176290-WDR25, 618059; MKRN3-MAGEL2, 605283; and KCNK9, 605874) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. The significant paternal parent-of-origin effect in delaying age of menarche at the MKRN3-MAGEL2 locus was associated with SNP rs12148769 (p(pat) = 2.4 x 10(-6)). It was unclear which of the genes explained this menarche signal.
In 14 (30%) of 46 probands with central precocious puberty, Simon et al. (2016) identified heterozygous mutations in the MKRN3 gene (see, e.g., 603856.0005). A previously reported frameshift mutation (603856.0004) was detected in 8 of the families, indicating a mutation hotspot.
Grandone et al. (2017) analyzed the MKRN3 gene in 60 girls with central precocious puberty and identified 3 heterozygous mutations in 3 probands (see, e.g., 603856.0005), for an overall prevalence of 5%.
In 3 sibs with central precocious puberty (CPPB2; 615346) and their unaffected father, Abreu et al. (2013) identified heterozygosity for a 1-bp deletion (c.637delC) in the MKRN3 gene, causing a frameshift predicted to result in a premature termination codon (Arg213GlyfsTer73) generating a truncated protein of 286 rather than 507 amino acids. The paternal grandmother, from whom DNA was not available, had a history of early menarche, suggesting that the unaffected father inherited the mutation from his mother but did not manifest the phenotype because only the paternally inherited MKRN3 allele is expressed. The mutation was not present in 3 other unaffected family members. The 2 sisters underwent thelarche at 5.75 and 6.5 years of age, and their brother had increased testicular volume at 8 years of age; all 3 sibs had pubertal levels of luteinizing hormone (LH; 152780), both basal and stimulated.
In 2 Brazilian sisters with central precocious puberty (CPPB2; 615346) and their affected father, paternal aunt, and paternal grandfather, Abreu et al. (2013) identified heterozygosity for a 1-bp insertion (c.1171_1172insA) in the MKRN3 gene, resulting in an immediate stop codon (Tyr391fsTer) that generates a protein of 391 amino acids rather than 507, lacking the last zinc finger motif.
In 3 affected sibs from a Belgian family with central precocious puberty (CPPB2; 615346), Abreu et al. (2013) identified heterozygosity for a c.1095G-T transversion in the MKRN3 gene, resulting in an arg365-to-ser (R365S) substitution at a highly conserved residue in the RING-type zinc finger. The mutation was inherited from their unaffected father; their mother was wildtype for MKRN3, and both parents had a history of normal pubertal development.
In 2 Brazilian brothers and a brother and sister from a family of European ancestry with central precocious puberty (CPPB2; 615346), Abreu et al. (2013) identified heterozygosity for a 1-bp insertion (c.475_476insC) in the MKRN3 gene, causing a frameshift predicted to result in a premature termination codon (Ala162GlyfsTer14) and a truncated protein of 176 amino acids. Consistent with the pattern of a paternally expressed imprinted gene, in both families the mutation was inherited from an unaffected father, who likely inherited it from his mother. Abreu et al. (2013) stated that it was possible that the 2 families were distantly related.
In 17 affected girls from 8 families with central precocious puberty, Simon et al. (2016) identified heterozygosity for the previously reported 1-bp insertion in the MKRN3 gene, which these authors designated as c.482insC, resulting in a premature termination codon (Ala162GlyfsTer15). The mutation segregated with disease in the families and was found in each of 6 unaffected carrier fathers tested. Noting the high frequency of this mutation, Simon et al. (2016) concluded that the cytosine homopolymer between nucleotides 476 and 482 is a mutation hotspot.
In 2 sisters and their unaffected father with central precocious puberty (CPPB2; 615346), Simon et al. (2016) identified heterozygosity for a c.982C-T transition in the MKRN3 gene, resulting in an arg328-to-cys (R328C) substitution. The mutation was not found in their unaffected mother or in the 1000 Genomes Project or NHLBI Exome Variant Server databases.
In a 7-year-old girl with central precocious puberty, Grandone et al. (2017) identified heterozygosity for the R328C mutation in the MKRN3 gene.
Abreu, A. P., Dauber, A., Macedo, D. B., Noel, S. D., Brito, V. N., Gill, J. C., Cukier, P., Thompson, I. R., Navarro, V. M., Gagliardi, P. C., Rodrigues, T., Kochi, C., and 9 others. Central precocious puberty caused by mutations in the imprinted gene MKRN3. New Eng. J. Med. 368: 2467-2475, 2013. [PubMed: 23738509] [Full Text: https://doi.org/10.1056/NEJMoa1302160]
Grandone, A., Capristo, C., Cirillo, G., Sasso, M., Umano, G. R., Mariani, M., Del Giudice, E. M., Perrone, L. Molecular screening of MKRN3, DLK1, and KCNK9 genes in girls with idiopathic central precocious puberty. Horm. Res. Paediat. 88: 194-200, 2017. [PubMed: 28672280] [Full Text: https://doi.org/10.1159/000477441]
Jong, M. T. C., Carey, A. H., Caldwell, K. A., Lau, M. H., Handel, M. A., Driscoll, D. J., Stewart, C. L., Rinchik, E. M., Nicholls, R. D. Imprinting of a RING zinc-finger encoding gene in the mouse chromosome region homologous to the Prader-Willi syndrome genetic region. Hum. Molec. Genet. 8: 795-803, 1999. [PubMed: 10196368] [Full Text: https://doi.org/10.1093/hmg/8.5.795]
Jong, M. T. C., Gray, T. A., Ji, Y., Glenn, C. C., Saitoh, S., Driscoll, D. J., Nicholls, R. D. A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader-Willi syndrome critical region. Hum. Molec. Genet. 8: 783-793, 1999. [PubMed: 10196367] [Full Text: https://doi.org/10.1093/hmg/8.5.783]
Nicholls, R. D., Saitoh, S., Horsthemke, B. Imprinting in Prader-Willi and Angelman syndromes. Trends Genet. 14: 194-200, 1998. [PubMed: 9613204] [Full Text: https://doi.org/10.1016/s0168-9525(98)01432-2]
Perry, J. R. B., Day, F., Elks, C. E., Sulem, P., Thompson, D. J., Ferreira, T., He, C., Chasman, D. I., Esko, T., Thorleifsson, G., Albrecht, E., Ang, W. Q., and 192 others. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature 514: 92-97, 2014. [PubMed: 25231870] [Full Text: https://doi.org/10.1038/nature13545]
Simon, D., Ba, I., Mekhail, N., Ecosse, E., Paulsen, A., Zenaty, D., Houang, M., Perelroizen, M. J., de Filippo, G.-P., Salerno, M., Simonin, G., Reynaud, R., Carel, J.-C., Leger, J., de Roux, N. Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty. Europ. J. Endocr. 174: 1-8, 2016. [PubMed: 26431553] [Full Text: https://doi.org/10.1530/EJE-15-0488]