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FB2026_03
,
released September 17, 2026
This report describes histiocytosis-lymphadenopathy plus syndrome, which is characterized by lymphatic system dysfunction and multiple variable phenotypes, including development of type 1 diabetes; this disease exhibits autosomal recessive inheritance. The human gene implicated in histiocytosis-lymphadenopathy plus syndrome is SLC29A3, which encodes an equilibrative nucleoside transporter, mediating both influx and efflux of nucleosides across the cell membrane. There are multiple equilibrative nucleoside transporters in both human and Drosophila; the fly gene most closely related to SLC29A3 is Dmel\Ent1. This Drosophila gene is also closely related to SLC29A1 and SLC29A2. RNAi targeting constructs and an allele caused by insertional mutagenesis have been generated for Dmel\Ent1.
The human SLC29A3 gene has not been introduced into flies.
Experiments with Drosophila have been designed primarily to assess interaction of SLC29A3 with insulin signaling pathways. Ubiquitous knockdown of Dmel\Ent1, effected by RNAi, results in lethality during the pupal and pharate adult stages. Mild knockdown results in flies that reach adulthood; they exhibit abnormal sensory bristle development. Genetic interactions of SLC29A3 with insulin signaling pathway genes (InR, Akt, Pi3K92E) have been characterized using a wing phenotype associated with Ent1 knockdown targeted to the wing. Ectopic expression of each of the tested genes results in rescue of the RNAi wing phenotype; expression of a dominant-negative form of Pi3K92E exacerbates the phenotype.
[updated Aug. 2018 by FlyBase; FBrf0222196]
[HISTIOCYTOSIS-LYMPHADENOPATHY PLUS SYNDROME](https://omim.org/entry/602782)
[SOLUTE CARRIER FAMILY 29 (NUCLEOSIDE TRANSPORTER), MEMBER 3: SLC29A3](https://omim.org/entry/612373)
The histiocytosis-lymphadenopathy plus syndrome comprises features of 4 histiocytic disorders previously thought to be distinct: H syndrome, pigmented hypertrichosis with insulin-dependent diabetes mellitus (PHID), Faisalabad histiocytosis, and familial Rosai-Dorfman disease (also known as sinus histiocytosis with massive lymphadenopathy or SHML). Because of the overlapping features and shared genetic cause, these disorders are now considered to be part of the same disease spectrum. [Genetics Home Reference, Histiocytosis-lymphadenopathy plus syndrome; 2018.08.31]
A feature common to the disorders in this spectrum is histiocytosis, which is the overgrowth of immune system phagocytic cells called histiocytes. The cells abnormally accumulate in one or more tissues in the body, which can lead to organ or tissue damage. The buildup often occurs in the lymph nodes, leading to swelling of the lymph nodes (lymphadenopathy). Other symptoms include patches of hyperpigmented skin with hypertrichosis and development of type 1 diabetes. [Genetics Home Reference, Histiocytosis-lymphadenopathy plus syndrome; 2018.08.31]
Histiocytosis-lymphadenopathy plus syndrome is caused by homozygous or compound heterozygous mutation in the SLC29A3 gene. [from MIM:602782; 2018.08.31]
Solute Carrier Family 29 Member 3 (SLC29A3) encodes a nucleoside transporter, playing a role in cellular uptake of nucleosides, nucleobases, and their related analogs. Solute carrier family 29 (SLC29) transporters are described as an equilibrative transporters, mediating both influx and efflux of nucleosides across the membrane. [Gene Cards, SLC29A3; 2018.08.31]
Many to many: 3 human to 2 Drosophila. The human genes are SLC29A3, SLC29A2, and SLC29A1.
High-scoring ortholog of human SLC29A1; moderate-scoring ortholog of SLC29A3 and SLC29A2 (2 Drosophila to 3 human). Dmel\Ent1 shares 29-34% identity and 50-52% similarity with the human genes.