ZFP57 – Transient Neonatal Diabetes Mellitus

Transient neonatal diabetes mellitus (TNDM) is a rare imprinting disorder characterized by early‐onset hyperglycemia that remits within months but may recur in later life. ZFP57 encodes a KRAB zinc‐finger protein essential for the maintenance of DNA methylation at multiple differentially methylated regions (DMRs) following fertilization. Loss of maternal ZFP57 function leads to multilocus imprinting disturbances (MLID) including loci controlling insulin regulation, manifesting clinically as TNDM.

Initial genetic evidence emerged from a genome-wide allelic methylation analysis in a TNDM patient harboring a 1-base‐pair deletion in ZFP57, which was associated with hypomethylation at multiple maternal DMRs and transient diabetes in the proband (1 proband)[PMID:23335487]. A subsequent comprehensive study of 55 MLID families identified 15 unique ZFP57 variants in affected offspring diagnosed with imprinting disorders, including TNDM (15 variants in 15 families)[PMID:35296332]. These variants comprised missense and truncating alleles predicted to disrupt ZFP57’s DNA‐binding capacity and maintenance of methylation marks.

Inheritance follows a maternal-effect pattern: mothers heterozygous for ZFP57 variants show no phenotype, but oocytes lacking functional ZFP57 produce offspring with MLID and TNDM. Segregation of ZFP57 alleles through multiple unrelated maternal lineages supports this mechanism, although formal segregation counts in TNDM kindreds remain limited.

Functionally, ZFP57 binds methylated TGCCGC motifs at imprinted DMRs and recruits the maintenance methylation machinery during early embryogenesis. Murine maternal‐knockout models recapitulate MLID and neonatal diabetes phenotypes, confirming a haploinsufficiency mechanism. Direct rescue experiments in human cellular systems have not yet been reported, limiting functional confirmation.

A screening of 30 Silver-Russell syndrome patients with isolated 11p15 hypomethylation found no pathogenic ZFP57 variants, arguing against a role in non-MLID imprinting disorders (no ZFP57 mutations)[PMID:19632365]. This specificity reinforces the association with multilocus imprinting defects leading to TNDM rather than solitary epimutations.

Integration of genetic and mechanistic data supports a Moderate clinical validity for ZFP57 in TNDM. Testing of ZFP57 in patients with TNDM and MLID informs reproductive counseling and guides early management decisions.

Key Take-home: Maternal-effect ZFP57 variants cause MLID and transient neonatal diabetes; genetic testing should be considered in TNDM cases with multilocus epimutations.

References

• Human mutation • 2013 • Genome-wide allelic methylation analysis reveals disease-specific susceptibility to multiple methylation defects in imprinting syndromes. PMID:23335487
• Clinical epigenetics • 2022 • Trans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences. PMID:35296332
• European journal of medical genetics • 2009 • Screening for genomic variants in ZFP57 in Silver-Russell syndrome patients with 11p15 epimutations. PMID:19632365

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