Alternative titles; symbols
HGNC Approved Gene Symbol: ZFP57
SNOMEDCT: 609579009;
Cytogenetic location: 6p22.1 Genomic coordinates (GRCh38) : 6:29,672,392-29,681,152 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p22.1 | Diabetes mellitus, transient neonatal 1 | 601410 | Autosomal dominant; Autosomal recessive | 3 |
KRAB zinc finger proteins, such as ZFP57, act as potent transcriptional repressors through KRAB box-mediated interaction with KAP1 (TRIM28; 601742) corepressor complexes. ZFP57 is a maternal-zygotic effect gene that contributes to the stable maintenance of methylation imprints during development (Li et al., 2008).
Okazaki et al. (1994) cloned cDNAs for 2 mouse Zfp57 transcripts that differed only in their 3-prime UTRs. Both transcripts encode a highly basic 421-amino acid protein containing 5 C2H2-type zinc finger motifs, followed by a putative nuclear localization signal and an acidic region at the C terminus. Northern blot analysis detected 2 transcripts in undifferentiated F9 mouse teratocarcinoma cells, but only 1 transcript was present in testis. No expression was detected in other adult mouse tissues. During mouse development, Zfp57 expression increased at embryonic day 11 and peaked at day 13. Immunohistochemical analysis revealed Zfp57 in the nucleus of F9 cells.
Alonso et al. (2004) cloned mouse and rat Zfp57. Both rodent proteins have an N-terminal KRAB domain with a highly divergent KRAB B region, 5 zinc finger motifs, a C-terminal nuclear localization signal, and numerous putative phosphorylation sites. During mouse and rat development, highest expression was detected in embryonic nerves and spinal cord, with lower expression in brain. Lung was the only non-neural tissue examined that expressed Zfp57 throughout development. Zfp57 expression in the nervous system dropped rapidly during the first few weeks after birth. Zfp57 localized to the nucleus of Schwann and other cells. In mouse fibroblasts, fluorescence-tagged Zfp57 colocalized with heterochromatin protein 1-alpha (CBX5; 604478) at centromeric heterochromatin in a speckled nuclear pattern, and this localization required the KRAB domain of Zfp57.
Mackay et al. (2008) found that the human ZFP57 gene encodes a protein of 516 amino acids that includes a predicted KRAB domain and 7 zinc fingers.
Using Northern blot analysis of adult mouse tissues, Li et al. (2008) found that Zfp57 was expressed predominantly in testis and ovary. In situ hybridization showed that Zfp57 expression in ovary was restricted to oocytes.
Mackay et al. (2008) found that the ZFP57 gene comprises 6 exons and spans 8.5 kb.
Mackay et al. (2008) mapped the ZFP57 gene to chromosome 6p22.1 by linkage analysis and genomic sequence analysis.
In 7 families with syndromic transient neonatal diabetes and hypomethylation of multiple imprinted loci (TNDM1; 601410), including the TND differentially methylated region (DMR) on chromosome 6q24, Mackay et al. (2008) identified missense, nonsense, and frameshift mutations in the ZFP57 gene. The variable but stable mosaicism of hypomethylation associated with ZFP57 mutation suggested that it has a role in maintenance of imprinted DNA methylation during the earliest multicellular stages of development.
Alonso et al. (2004) showed that rodent Zfp57 repressed transcription. Zfp57 expression was upregulated in Schwann cells in response to leukemia-inhibitory factor (LIF; 159540) and Fgf2 (134920).
Using coimmunoprecipitation analysis, Li et al. (2008) showed that mouse Zfp57 interacted with the corepressor Kap1 in transfected COS cells. Binding between endogenous Zfp57 and Kap1 was confirmed in mouse embryonic stem cells.
Mackay et al. (2008) noted that ZFP57 is expressed in pluripotent murine embryonic stem cells (Ramalho-Santos et al., 2002; Ivanova et al., 2002) and is a functional target of STAT3 (102582) and POU5F1 (164177), although it is in itself dispensable for maintenance of stem cell pluripotency and self-renewal (Akagi et al., 2005). The variable but stable mosaicism of hypomethylation associated with ZFP57 mutation suggested to Mackay et al. (2008) that it has a role in maintenance of imprinted DNA methylation during the earliest multicellular stages of development.
Li et al. (2008) found that Zfp57 deletion in mice resulted in a high degree of embryonic and neonatal lethality. Analysis of percent of lethality in the offspring of all possible matings of wildtype, Zfp57 -/-, and Zfp57 +/- animals, as well as of crosses with oocytes in which Zfp57 was conditionally ablated, revealed that the percent of lethality in any litter depended on both the dosage and parent of origin of the deletion. Mutant oocytes from Zfp57 -/- females lacked maternal imprinting at the Snrpn locus (182279), but imprints at other maternally methylated regions were normal. Deletion of Zfp57 in the male germline had no effect on paternal imprint patterns. In the zygote, acquisition of a normal paternal Zfp57 allele rescued imprinting of maternally derived Snrpn and resulted in zygote and embryonic viability. However, mating between Zfp57 -/- animals resulted in complete embryonic lethality, with defective imprinting at the maternal Snrpn locus and at several paternal imprinted regions.
In 2 children with transient neonatal diabetes (TNDM1; 601410) from a consanguineous union, Mackay et al. (2008) identified homozygosity for a C-to-A transversion at nucleotide 723 of the ZFP57 gene, resulting in a cys-to-stop codon substitution at amino acid 241 (C241X). One patient, evaluated at 6 years of age, had presented with neonatal diabetes which required insulin for the first 7 months of life, microcephaly, and herniated umbilical cord. She also had patent ductus arteriosus, bilateral postaxial polydactyly of the hands, bilateral hypermetropia, macroglossia, and mild developmental delay. Relapse of diabetes occurred at 2 years and 8 months of age. The second patient, who died at 11 months of age, had neonatal diabetes requiring insulin until death, microcephaly and intrauterine growth retardation (birth weight 2,000 grams), umbilical hernia, septal defect, macroglossia, tracheomalacia, severe epilepsy, and cerebral blindness. These patients had been described by Boonen et al. (2008), who found a mosaic spectrum of hypomethylation at multiple maternally methylated loci.
In a consanguineous family with transient neonatal diabetes (TNDM1; 601410), Mackay et al. (2008) identified a 2-bp deletion of AG at nucleotides 257 and 258 of the ZFP57 gene (257_258delAG), resulting in a frameshift and premature termination 28 amino acids after codon 86 (Glu86ValfsTer28). The proband was identified at 5 months of age. He had had transient neonatal diabetes requiring insulin for the first 3.5 months. He had normal growth and development at that age with no syndromic features. His father at age 38 years was ascertained through family studies. He had no early history of diabetes; birth parameters were unknown. He was healthy at 38 years of age without evidence of diabetes.
In a 6-month-old child with transient neonatal diabetes (TNDM1; 601410) from a consanguineous union, Mackay et al. (2008) identified homozygosity for a single-nucleotide deletion at nucleotide 1323 of the ZFP57 gene (1323delC). This resulted in a frameshift and termination codon 17 amino acids downstream (Gly441GlyfsTer17). The baby required insulin for the first 4 months. He was born small for gestational age and had clinodactyly, bilateral failure of flexion at interphalangeal joints of the fifth digit, possible epilepsy with roving eye movements, and suspected cerebral blindness. He had severe developmental delay and was developing cerebellar palsy. MRI showed partial agenesis of corpus callosum, dilatation of temporal horns, and hypoplasia of cerebellar vermis. He had micrognathia despite macroglossia.
In an 18-month-old fraternal twin with transient neonatal diabetes (TNDM1; 601410) from a consanguineous union, Mackay et al. (2008) identified a homozygous C-to-G transversion at nucleotide 1312 of the ZFP57 gene resulting in a histidine-to-aspartic acid substitution at codon 438 (H438D). The histidine at codon 438 is completely conserved throughout evolution. The patient had transient neonatal diabetes that required insulin for the first month of life. He was born small for gestational age and had macroglossia, tetralogy of Fallot, and mild developmental delay. No neurologic imaging was done.
In a male child with transient neonatal diabetes (TNDM1; 601410) from a consanguineous union, Mackay et al. (2008) identified homozygosity for a G-to-A transition at nucleotide 683 of the ZFP57 gene, resulting in an arg-to-his substitution at codon 228 (R228H). The arginine at this location is conserved throughout evolution. The patient was 11 years of age at the time of the report. He required insulin for the first 4 months of life and had mild developmental delay. Other than a hydrocele and 1 neonatal seizure, he had been healthy. This mutation was also found in compound heterozygosity in another patient with syndromic transient neonatal diabetes (see 612192.0007).
In a 23-year-old female who had had transient neonatal diabetes (TNDM1; 601410), Mackay et al. (2008) identified a histidine-to-asparagine substitution at codon 257 of the ZFP57 gene (H257N) due to a C-to-A transversion at nucleotide 769. The histidine at codon 257 is completely evolutionarily conserved in species from opossum to human. The patient required insulin for the first 4 months of life and had macroglossia. She grew and developed normally until a relapse of diabetes at 12 years, 6 months of age.
In a male child with syndromic transient neonatal diabetes (TNDM1; 601410), the product of a nonconsanguineous union, Mackay et al. (2008) identified compound heterozygosity for an R228H mutation (612192.0005) and a frameshift mutation deleting 8 nucleotides after nucleotide 838 (838_845delACCCAGGC), resulting in a frameshift following codon 279 (279fsTer1). The patient required insulin for the first 4 months, was born with an umbilical hernia, and had macroglossia. He had mild hemihypertrophy of the left arm, pectus carinatum, and clinodactyly. He did not walk until 2 years of age and had mild developmental delay requiring special education; specific problems with oromotor dyspraxia, difficulties with expressive language, slow writing, and problems with tripod grip were present. He had mild progressive contractures at wrist, elbow, knees, ankles, and toes, affecting gait. Electromyographic studies (EMG) showed neurogenic changes, and muscle biopsy showed variation in fiber size.
Akagi, T., Usuda, M., Matsuda, T., Ko, M. S. H., Niwa, H., Asano, M., Koide, H., Yokota, T. Identification of Zfp-57 as a downstream molecule of STAT3 and Oct-3/4 in embryonic stem cells. Biochem. Biophys. Res. Commun. 331: 23-30, 2005. [PubMed: 15845352] [Full Text: https://doi.org/10.1016/j.bbrc.2005.03.118]
Alonso, M. B. D., Zoidl, G., Taveggia, C., Bosse, F., Zoidl, C., Rahman, M., Parmantier, E., Dean, C. H., Harris, B. S., Wrabetz, L., Mueller, H. W., Jessen, K. R., Mirsky, R. Identification and characterization of ZFP-57, a novel zinc finger transcription factor in the mammalian peripheral nervous system. J. Biol. Chem. 279: 25653-25664, 2004. [PubMed: 15070898] [Full Text: https://doi.org/10.1074/jbc.M400415200]
Boonen, S. E., Porksen, S., Mackay, D. J. G., Oestergaard, E., Olsen, B., Brondum-Nielsen, K., Temple, I. K., Hahnemann, J. M. D. Clinical characterisation of the multiple maternal hypomethylation syndrome in siblings. Europ. J. Hum. Genet. 16: 453-461, 2008. [PubMed: 18197189] [Full Text: https://doi.org/10.1038/sj.ejhg.5201993]
Ivanova, N. B., Dimos, J. T., Schaniel, C., Hackney, J. A., Moore, K. A., Lemischka, I. R. A stem cell molecular signature. Science 298: 601-604, 2002. [PubMed: 12228721] [Full Text: https://doi.org/10.1126/science.1073823]
Li, X., Ito, M., Zhou, F., Youngson, N., Zuo, X., Leder, P., Ferguson-Smith, A. C. A maternal-zygotic effect gene, Zfp57, maintains both maternal and paternal imprints. Dev. Cell 15: 547-557, 2008. [PubMed: 18854139] [Full Text: https://doi.org/10.1016/j.devcel.2008.08.014]
Mackay, D. J. G., Callaway, J. L. A., Marks, S. M., White, H. E., Acerini, C. L., Boonen, S. E., Dayanikli, P., Firth, H. V., Goodship, J. A., Haemers, A. P., Hahnemann, J. M. D., Kordonouri, O., Masoud, A. F., Oestergaard, E., Storr, J., Ellard, S., Hattersley, A. T., Robinson, D. O., Temple, I. K. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nature Genet. 40: 949-951, 2008. [PubMed: 18622393] [Full Text: https://doi.org/10.1038/ng.187]
Okazaki, S., Tanase, S., Choudhury, B. K., Setoyama, K., Miura, R., Ogawa, M., Setoyama, C. A novel nuclear protein with zinc fingers down-regulated during early mammalian cell differentiation. J. Biol. Chem. 269: 6900-6907, 1994. [PubMed: 8120052]
Ramalho-Santos, M., Yoon, S., Matsuzaki, Y., Mulligan, R. C., Melton, D. A. 'Stemness': transcriptional profiling of embryonic and adult stem cells. Science 298: 597-600, 2002. [PubMed: 12228720] [Full Text: https://doi.org/10.1126/science.1072530]