Journal Article

<i>SLC29A3</i> gene is mutated in pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome and interacts with the insulin signaling pathway

Simon T. Cliffe, Jamie M. Kramer, Khalid Hussain, Joris H. Robben, Eiko K. de Jong, Arjan P. de Brouwer, Esther Nibbeling, Erik-Jan Kamsteeg, Melanie Wong, Julie Prendiville, Chela James, Raja Padidela, Charlie Becknell, Hans van Bokhoven, Peter M.T. Deen, Raoul C.M. Hennekam, Robert Lindeman, Annette Schenck, Tony Roscioli and Michael F. Buckley

in Human Molecular Genetics

Volume 18, issue 12, pages 2257-2265
Published in print June 2009 | ISSN: 0964-6906
Published online March 2009 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddp161
SLC29A3 gene is mutated in pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome and interacts with the insulin signaling pathway

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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.

Journal Article.  5450 words.  Illustrated.

Subjects: Genetics and Genomics

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