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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.

human molecular genetics

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