Further refinement of the critical minimal genetic region for the imprinting disorder 6q24 transient neonatal diabetes

Abstract

Aims/hypothesis Transient neonatal diabetes (TND) is associated with overexpression of genes within a critical region on 6q24. This study aims to refine the boundaries of this region to reduce the number of potential candidate genes for 6q24 TND. Methods Fifteen patients with transient neonatal diabetes and submicroscopic chromosome 6 duplications were investigated. The duplications were confirmed by microsatellite analysis and subsequently mapped using tiled chromosome 6 array Comparative Genomic Hybridisation (aCGH) and MLPA. Duplication boundaries were compared to identify the minimal shared region of duplication.These data were then used with available clinical data to identify associations between size of 6q24 duplication and severity of TND phenotype. Results Alignment of the minimal region of duplication to the human genome reduced the minimal TND critical region, formerly estimated at 440 kb, to 160-173 kb, revealing PLAGL1 (pleiomorphic adenoma gene-like 1) and HYMAI (imprinted in hydatidiform mole) to be the only genes wholly included therein. Additionally, the complete paternal duplication of a region containing the theoretical protein FAM164B was associated with the severe growth restriction observed in 6q24 duplication patients. Conclusions/interpretation This study has significantly reduced the critical region associated with 6q24 TND. It has eliminated several previous TND candidate genes, leaving the overlapping imprinted genes PLAGL1 and HYMAI as the only remaining complete candidate genes for 6q24 TND. Moreover, these data provide the first evidence that an additional region, encompassing the theoretical protein FAM164B, may have a critical role in the growth restriction phenotype observed in many 6q24 TND patients.

Epigenetics and imprinting in human disease

“…1 (Azzi et al, 2014); 2 (Cassidy et al, 2012, Mabb et al, 2011; 3 (Ankolkar et al, 2013, Docherty et al, 2010, Iglesias-Platas et al, 2013, Kamikihara et al, 2005; 4 (Lecumberri et al, 2010, Linglart et al, 2013, Turan and Bastepe, 2013; 5 (Huang et al, 2007, Jorgensen et al, 2013, Kawakami et al, 2006, Sutton and Shaffer, 2000; 6 (Dowdy et al, 2005, Trouillard et al, 2004, Van den Veyver et al, 2001; 7 (Gao et al, 2010, Tsou et al, 2003; 8 (Kobayashi et al, 1997, Lee andBartolomei, 2013); 9 (Hysi et al, 2010, Takamaru et al, 2012, Tarnowski et al, 2012, Zhu et al, 2013 methylation and biallelic expression of imprinted genes (Kaneda et al, 2004). Through the use of the de novo DNA methyltransferases DNMT3A and DNMT3B and the accessory protein DNMT3L, ICRs and DMRs are specifically methylated in the male or female germline (Bartolomei and Ferguson-Smith, 2011).…”

“…Mis-expression can be due to mutations in imprinted genes, methylation defects at ICRs or other regulatory regions, or uniparental disomy (UPD), where an imprinted chromosomal region from one parent is replaced by the same chromosomal region from the other parent. In some cases, overexpression of paternally expressed genes leads to disease, for example, on chromosome 6q24 resulting in transient neonatal diabetes mellitus type I (Docherty et al, 2010). Alternatively, the failure to express the maternal alleles can lead to disease, as demonstrated by chromosome 20q13.32 where loss of maternal gene expression causes pseudohypoparathyroidism (Lecumberri et al, 2010).…”

Insulin pump therapy in transient neonatal diabetes mellitus

“…These mutations result in overactive channels, leading to hyperpolarization of β cells and reduced insulin secretion. On the other hand, abnormalities in chromosome 6 including paternal uniparental disomy and duplication of 6q24 on the paternal allele have been demonstrated in patients with TNDM2,10,11). Overexpression of imprinted genes at 6q24 ( PLAGL1 and HYMAI ) has been reported to result in TNDM6).…”

Translational implications of the β-cell epigenome in diabetes mellitus

“…Three genetic categories of TND have been identified, and these include paternal uniparental disomy of chromosome 6, duplication of the 6q24 region, or loss of maternal methylation of an imprinted 6q24 CpG island (36). While the gene product responsible for TND has not been definitively identified, the 6q24 region contains both an untranslated transcript with no known function as well as the gene for pleomorphic adenoma gene 1 (PLAG1 or ZAC) (37). PLAG1 or ZAC is a zinc finger transcription factor that serves as the leading gene candidate for TND and has been linked to regulation of cell cycle and apoptosis.…”