Mutations in SLC29A3, Encoding an Equilibrative Nucleoside Transporter ENT3, Cause a Familial Histiocytosis Syndrome (Faisalabad Histiocytosis) and Familial Rosai-Dorfman Disease

Abstract

The histiocytoses are a heterogeneous group of disorders characterised by an excessive number of histiocytes. In most cases the pathophysiology is unclear and treatment is nonspecific. Faisalabad histiocytosis (FHC) (MIM 602782) has been classed as an autosomal recessively inherited form of histiocytosis with similarities to Rosai-Dorfman disease (RDD) (also known as sinus histiocytosis with massive lymphadenopathy (SHML)). To elucidate the molecular basis of FHC, we performed autozygosity mapping studies in a large consanguineous family and identified a novel locus at chromosome 10q22.1. Mutation analysis of candidate genes within the target interval identified biallelic germline mutations in SLC29A3 in the FHC kindred and in two families reported to have familial RDD. Analysis of SLC29A3 expression during mouse embryogenesis revealed widespread expression by e14.5 with prominent expression in the central nervous system, eye, inner ear, and epithelial tissues including the gastrointestinal tract. SLC29A3 encodes an intracellular equilibrative nucleoside transporter (hENT3) with affinity for adenosine. Recently germline mutations in SLC29A3 were also described in two rare autosomal recessive disorders with overlapping phenotypes: (a) H syndrome (MIM 612391) that is characterised by cutaneous hyperpigmentation and hypertrichosis, hepatomegaly, heart anomalies, hearing loss, and hypogonadism; and (b) PHID (pigmented hypertrichosis with insulin-dependent diabetes mellitus) syndrome. Our findings suggest that a variety of clinical diagnoses (H and PHID syndromes, FHC, and familial RDD) can be included in a new diagnostic category of SLC29A3 spectrum disorder.

Human Equilibrative Nucleoside Transporter-3 (hENT3) Spectrum Disorder Mutations Impair Nucleoside Transport, Protein Localization, and Stability

“…H syndrome and pigmented hypertrichotic dermatosis with insulin-dependent diabetes (PHID) 3 syndrome are recently described autosomal-recessive genetic disorders in humans (1,2). H syndrome patients display symptoms such as cutaneous hyperpigmentation, hypertrichosis, heart anomalities, hearing loss, hepatomegaly hypogonadism, and etc.…”

The histopathology and phenotypic variability in H syndrome

“…Phenotypic variability in H syndrome further emphasizes the need for diagnostic measures. The c.G1309>A mutation has been associated with multiple abnormalities including short stature, exophthalmos, dilated lateral scleral vasculature, hearing loss, congenital cardiac anomalies, hepatomegaly, hypogonadism, varicose veins, fixed flexion, hallux valgus, flat foot, malabsorption, and hyperglycemia 1, 6, 7, 8, 9, 10, 11, 12. Our patient had only hearing loss, a prominent feature of this syndrome 8.…”

Inhibition of Transient Receptor Potential Channel Mucolipin-1 (TRPML1) by Lysosomal Adenosine Involved in Severe Combined Immunodeficiency Diseases

“…3D). Interestingly, overexpression of ENT3 but not ENT3-G437R, a mutant ENT3 with compromised transport activity but normal subcellular localization (8,33), rescued the compromised Fura-2 response induced by ML-SA1 (Fig. 3, B and C) in ADA Ϫ/Ϫ fibroblasts without changing lysosomal Ca 2ϩ content (Fig.…”