HGNC Approved Gene Symbol: HYMAI
Cytogenetic location: 6q24.2 Genomic coordinates (GRCh38) : 6:144,004,916-144,008,259 (from NCBI)
Transient neonatal diabetes mellitus (TNDM; 601410) is a rare disease characterized by intrauterine growth retardation, dehydration, and failure to thrive due to a lack of normal insulin secretion. This disease is associated with paternal uniparental disomy or paternal duplication of chromosome 6, suggesting that the causative gene(s) for TNDM may be imprinted. By database searching for ESTs that mapped to the TNDM candidate region on 6q24.1-q24.3, followed by RT-PCR analysis using monochromosomal hybrid cells with a human chromosome 6 of defined parental origin, Arima et al. (2000) identified a novel imprinted gene at 6q24, which they named hydatidiform mole-associated and imprinted transcript (HYMAI). The gene, which generates an untranslated mRNA, exhibits differential DNA methylation between the 2 parental alleles at an adjacent CpG island and is expressed only from the paternal chromosome. A previously characterized imprinted gene, ZAC/LOT1 (PLAGL1; 603044), is located 70 kb downstream of HYMAI and is also expressed only from the paternal allele. In the pancreas, both genes were moderately expressed. The authors proposed that HYMAI and ZAC/LOT1 are candidate genes for involvement in TNDM.
Arima et al. (2000) identified the HYMAI gene on 6q24, within the critical region for TNDM.
Arima et al. (2001) showed that the differentially methylated CpG island that partially overlaps Zac1 and Hymai at the syntenic mouse locus is a likely imprinting control region (ICR) for the 120- to 200-kb domain. The region is unmethylated in sperm but probably methylated in oocytes, a difference that persists between parental alleles throughout pre- and postimplantation development. Within this ICR, there is a region that exhibits a high degree of homology between mouse and human and acts as a strong transcriptional repressor when methylated. In 5 of 6 TNDM patients with a normal karyotype studied, loss of methylation at 8 CpG sites within the region was demonstrated. ZAC is a transcriptional regulator of the type 1 receptor for pituitary adenylate cyclase-activating polypeptide (102981), a potent insulin secretagogue and an important mediator of autocrine control of insulin secretion in the pancreatic islet. The authors proposed that the ICR adjacent to ZAC may regulate expression of imprinted genes within the domain, and that epigenetic or genetic mutations of this region probably result in TNDM by affecting expression of ZAC in the pancreas and/or the pituitary.
Mackay et al. (2002) demonstrated imprinted expression of the ZAC and HYMAI genes in cases of TNDM.
Arima et al. (2006) found that a transgene carrying the human HYMAI/PLAGL1 differentially methylated CpG island was methylated in the correct parent origin-specific manner in mice, and that this methylation was sufficient to confer imprinted expression from the transgene. They concluded that the differentially methylated CpG island functions as the imprinting center for the HYMAI/PLAGL1 imprinted domain.
Arima, T., Drewell, R. A., Oshimura, M., Wake, N., Surani, M. A. A novel imprinted gene, HYMAI, is located within an imprinted domain on human chromosome 6 containing ZAC. Genomics 67: 248-255, 2000. [PubMed: 10936046] [Full Text: https://doi.org/10.1006/geno.2000.6266]
Arima, T., Drewell, R., Arney, K. L., Inoue, J., Makita, Y., Hata, A., Oshimura, M., Wake, N., Surani, M. A. A conserved imprinting control region at the HYMAI/ZAC domain is implicated in transient neonatal diabetes mellitus. Hum. Molec. Genet. 10: 1475-1483, 2001. [PubMed: 11448939] [Full Text: https://doi.org/10.1093/hmg/10.14.1475]
Arima, T., Yamasaki, K., John, R. M., Kato, K., Sakumi, K., Nakabeppu, Y., Wake, N., Kono, T. The human HYMAI/PLAGL1 differentially methylated region acts as an imprint control region in mice. Genomics 88: 650-658, 2006. [PubMed: 16928428] [Full Text: https://doi.org/10.1016/j.ygeno.2006.07.005]
Mackay, D. J. G., Coupe, A.-M., Shield, J. P. H., Storr, J. N. P., Temple, I. K., Robinson, D. O. Relaxation of imprinted expression of ZAC and HYMAI in a patient with transient neonatal diabetes mellitus. Hum. Genet. 110: 139-144, 2002. [PubMed: 11935319] [Full Text: https://doi.org/10.1007/s00439-001-0671-5]