Transient neonatal diabetes : multilocus methylation defects associated with novel ZFP57 mutation

Introduction: Transient neonatal diabetes (TND) is a rare imprinting disorder. Affected infants are often found to be hyperglycemic during the first 6 months of life. TND molecular aetiology is attributable to defects causing... [ view full abstract ]

Introduction: Transient neonatal diabetes (TND) is a rare imprinting disorder. Affected infants are often found to be hyperglycemic during the first 6 months of life. TND molecular aetiology is attributable to defects causing overexpression of the paternally inherited PLAGL1 and HYMAI genes on chromosome 6q24. Over 50% of patients with hypomethylation at the TNDM locus have additional hypomethylation of other imprinted genes (multilocus imprinting disturbances, MLID). In a proportion of these patients, recessive mutations in ZFP57 gene are identified.

Methods: We report an affected Tunisian male child who had hyperglycemia and mild dysmorphism consisting in macrostomia and macroglossia. We studied at first the methylation status of the paternally 6q24 imprinted locus. Then, in order to investigate MLID, 5 maternally (7q32, 7p12, 11p15.5, 15q11-13 and 20q13.3) and 3 paternally (11p15.5, 14q32 and 15q11-13) imprinted loci were analyzed. 

Results: Methylation testing revealed, at 6q24 locus, a complete hypomethylation confirming the diagnosis of TND. Additionally, the patient was totally hypomethylated at 7p12 locus and partially hypomethylated at 7q32 and 20q13.3 loci. Coding regions of ZFP57, with intron-exon boundaries, were sequenced in our TND-MLID patient and his parents. The patient was carrier of a novel nonsense mutation (c.373C>T; p.Arg125*). The truncating substitution was heterozygously found in the parents.

Discussion :ZFP57 encodes a zinc-finger transcription factor expressed in early development. It plays a critical role in the maintenance of DNA methylation at multiple imprinting control regions. Here we provide additional support of the role of ZFP57 gene as an important genetic determinant for the diagnosis of TND-MLID is underlined.