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.
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.
Authors: M Kamiya; H Judson; Y Okazaki; M Kusakabe; M Muramatsu; S Takada; N Takagi; T Arima; N Wake; K Kamimura; K Satomura; R Hermann; D T Bonthron; Y Hayashizaki Journal: Hum Mol Genet Date: 2000-02-12 Impact factor: 6.150
Authors: A Varrault; B Bilanges; D J Mackay; E Basyuk; B Ahr; C Fernandez; D O Robinson; J Bockaert; L Journot Journal: J Biol Chem Date: 2001-04-10 Impact factor: 5.157
Authors: R J Gardner; D J Mackay; A J Mungall; C Polychronakos; R Siebert; J P Shield; I K Temple; D O Robinson Journal: Hum Mol Genet Date: 2000-03-01 Impact factor: 6.150
Authors: Dan Ma; Julian P H Shield; Wendy Dean; Isabelle Leclerc; Claude Knauf; R éMy Burcelin R; Guy A Rutter; Gavin Kelsey Journal: J Clin Invest Date: 2004-08 Impact factor: 14.808
Authors: Sarah E Flanagan; Ann-Marie Patch; Deborah J G Mackay; Emma L Edghill; Anna L Gloyn; David Robinson; Julian P H Shield; Karen Temple; Sian Ellard; Andrew T Hattersley Journal: Diabetes Date: 2007-04-19 Impact factor: 9.461
Authors: Jennifer M Kalish; Laura K Conlin; Tricia R Bhatti; Holly A Dubbs; Mary Catherine Harris; Kosuke Izumi; Sogol Mostoufi-Moab; Surabhi Mulchandani; Sulagna Saitta; Lisa J States; Daniel T Swarr; Alisha B Wilkens; Elaine H Zackai; Kristin Zelley; Marisa S Bartolomei; Kim E Nichols; Andrew A Palladino; Nancy B Spinner; Matthew A Deardorff Journal: Am J Med Genet A Date: 2013-06-26 Impact factor: 2.802