Ameni Touati1,2, Javier Errea-Dorronsoro3, Sonia Nouri4,5, Yosra Halleb1,5, Arrate Pereda3, Nabiha Mahdhaoui4,5, Aida Ghith4,5, Ali Saad1,5, Guiomar Perez de Nanclares3, Dorra H'mida Ben Brahim6,7. 1. Department of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat HACHED University Hospital, 4000, Sousse, Tunisia. 2. High Institute of Biotechnology, Monastir University, Monastir, Tunisia. 3. Molecular (Epi)Genetic Lab, BioAraba National Health Institute, OSI Araba University Hospital, 01009, Vitoria-Gasteiz, Alava, Spain. 4. Department of Neonatology, Farhat HACHED University Hospital, 4000, Sousse, Tunisia. 5. Faculty of Medicine, Sousse University, Sousse, Tunisia. 6. Department of Human Cytogenetics, Molecular Genetics and Reproductive Biology, Farhat HACHED University Hospital, 4000, Sousse, Tunisia. dorrahmida@yahoo.fr. 7. Faculty of Medicine, Sousse University, Sousse, Tunisia. dorrahmida@yahoo.fr.
Abstract
AIM: 6q24-related transient neonatal diabetes mellitus (6q24-TNDM) is a rare imprinting disorder characterized by uncontrolled hyperglycemia during the first 6 months of life. The molecular etiology of 6q24-TNDM is attributable to overexpression of the paternally inherited PLAGL1 and HYMAI genes located on the 6q24 locus. One of these major defects is maternal loss of methylation (LOM) at 6q24. In addition, approximately 50% of TNDM patients that present LOM at 6q24 can also display hypomethylation at additional imprinted loci (multilocus imprinting disturbances, MLID). Interestingly, the majority of these patients carry mutations in the ZFP57 gene, a transcription factor required for the adequate maintenance of methylation during early embryonic development. METHODS: Methylation analysis of 6q24 and additional imprinted loci was carried out by MS-MLPA in a Tunisian male patient with clinical diagnosis of TNMD. For the same patient, mutation analysis of the ZFP57 gene was conducted by direct Sanger sequencing. RESULTS: We report a novel nonsense mutation (c.373C > T; p.R125*; ENST00000376883.1) at the ZFP57 gene causing TNDM-MLID and describe detailed phenotype/epigenotype analysis of TNMD patients carrying ZFP57 mutations. CONCLUSION: We provide additional support to the role of ZFP57 as a genetic determinant cause of MLID in patients with TNMD.
AIM: 6q24-related transient neonatal diabetes mellitus (6q24-TNDM) is a rare imprinting disorder characterized by uncontrolled hyperglycemia during the first 6 months of life. The molecular etiology of 6q24-TNDM is attributable to overexpression of the paternally inherited PLAGL1 and HYMAI genes located on the 6q24 locus. One of these major defects is maternal loss of methylation (LOM) at 6q24. In addition, approximately 50% of TNDMpatients that present LOM at 6q24 can also display hypomethylation at additional imprinted loci (multilocus imprinting disturbances, MLID). Interestingly, the majority of these patients carry mutations in the ZFP57 gene, a transcription factor required for the adequate maintenance of methylation during early embryonic development. METHODS: Methylation analysis of 6q24 and additional imprinted loci was carried out by MS-MLPA in a Tunisian male patient with clinical diagnosis of TNMD. For the same patient, mutation analysis of the ZFP57 gene was conducted by direct Sanger sequencing. RESULTS: We report a novel nonsense mutation (c.373C > T; p.R125*; ENST00000376883.1) at the ZFP57 gene causing TNDM-MLID and describe detailed phenotype/epigenotype analysis of TNMDpatients carrying ZFP57 mutations. CONCLUSION: We provide additional support to the role of ZFP57 as a genetic determinant cause of MLID in patients with TNMD.
Authors: Ana Monteagudo-Sánchez; Jose Ramon Hernandez Mora; Carlos Simon; Adam Burton; Jair Tenorio; Pablo Lapunzina; Stephen Clark; Manel Esteller; Gavin Kelsey; Juan Pedro López-Siguero; Guiomar Perez de Nanclares; Maria-Elena Torres-Padilla; David Monk Journal: Nucleic Acids Res Date: 2020-11-18 Impact factor: 16.971