Human Molecular Genetics Advance Access originally published online on March 31, 2009
Human Molecular Genetics 2009 18(12):2257-2265; doi:10.1093/hmg/ddp161
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SLC29A3 gene is mutated in pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome and interacts with the insulin signaling pathway
1 Department of Haematology and Genetics, South Eastern Area Laboratory Services, Sydney, NSW 2031, Australia 2 Centre for Vascular Research, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia 3 Department of Human Genetics, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands 4 Department of Gastroenterology, Endocrinology, Metabolism and Adolescent Medicine, Institute of Child Health, UCL, London WC1N 1EH, UK 5 Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands 6 Division of Immunology and Allergy, Children's Hospital, Westmead, NSW 2145, Australia 7 Division of Pediatric Dermatology, British Columbia's Children's Hospital, Vancouver, BC, Canada V6H 3V4 8 Dermatology Associates of Kentucky, Lexington, KY 40509, USA 9 Clinical and Molecular Genetics Unit, Institute of Child Health, UCL, London WC1N 1EH, UK
* To whom correspondence should be addressed. Tel: +31 243610712; Fax: +31 243616658; Email: m.buckley{at}antrg.umcn.nl
Received January 26, 2009; Accepted March 26, 2009
Pigmented hypertrichotic dermatosis with insulin-dependent diabetes (PHID) syndrome is a recently described autosomal recessive disorder associated with predominantly antibody negative, insulin-dependent diabetes mellitus. In order to identify the genetic basis of PHID and study its relationship with glucose metabolism, we performed homozygosity mapping in five unrelated families followed by candidate gene sequencing. Five loss-of-function mutations were identified in the SLC29A3 gene which encodes a member of a highly conserved protein family that transports nucleosides, nucleobases and nucleoside analogue drugs, hENT3. We show that PHID is allelic with a related syndrome without diabetes mellitus, H syndrome. The interaction of SLC29A3 with insulin signaling pathways was then studied using an established model in Drosophila melanogaster. Ubiquitous knockdown of the Drosophila ortholog of hENT3, dENT1 is lethal under stringent conditions; whereas milder knockdown induced scutellar bristle phenotypes similar to those previously reported in the knockdown of the Drosophila ortholog of the Islet gene. A cellular growth assay showed a reduction of cell size/number which could be rescued or enhanced by manipulation of the Drosophila insulin receptor and its downstream signaling effectors, dPI3K and dAkt. In summary, inactivating mutations in SLC29A3 cause a syndromic form of insulin-dependent diabetes in humans and in Drosophila profoundly affect cell size/number through interactions with the insulin signaling pathway. These data suggest that further investigation of the role of SLC29A3 in glucose metabolism is a priority for diabetes research.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.