The H syndrome is caused by mutations in the nucleoside transporter hENT3

Abstract

The H syndrome is a recently reported autosomal-recessive disorder characterized by cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature, hallux valgus, and fixed flexion contractures of the toe joints and the proximal interphalangeal joints. Homozygosity mapping in five consanguineous families resulted in the identification of mutations in the SLC29A3 gene, which encodes the equilibrative nucleoside transporter hENT3. Three mutations were found in 11 families of Arab and Bulgarian origin. The finding of several different mutations in a small geographic region implies that the H syndrome might be rather common. The identification of mutations in the SLC29A3 gene in patients with a mild clinical phenotype suggests that this is a largely underdiagnosed condition and strongly suggests that even oligosymptomatic individuals might have the disorder.

Figure 1

Pedigrees and Clinical Findings of Four Novel Families with H Syndrome and of a Previously Reported Bulgarian Family Affected individuals are marked by gray symbols. Pedigrees for families G–K are shown at left. (A) Hyperpigmentation of inner thighs in patient GII-3. (B) More diffuse and extensive hyperpigmentation in patient KII-1. (C) Fixed flexion contractures of proximal interphalangeal joints in patient HII-2. (D) Hallux valgus and fixed flexion contractures of toe joints in patient III-6.

Figure 2

Haplotype Analysis Performed in Six Families with H Syndrome Affected individuals are marked by gray symbols. The disease-associated haplotypes in the linked interval on chromosome 10q21.3–q22.1 are shown by vertical bars (red and green) in families A–F. Alleles excluded by recombination events are marked in pink. The physical locations of the polymorphic microsatellites are given near the haplotype for individual AI-2.

Figure 3

Mutations c.1279G > A, c.1309G > A, and c.1045delC in the SLC29A3 Gene (A) Conservation among species of amino acid positions affected by G427S and G437R missense mutations. The mutated amino acids are marked by blue and red, respectively. (B) The single base-pair substitution mutations are shown (vertical arrow) in DNA samples of patients CII-2 (c.1309G > A), BII-3 (c.1279G > A), and AII-8 (c.1309G > A; c.1279G > A). The wild-type is shown in the upper panel. (C) The c.1045delC mutation in patient JII-1 is shown in the lower panel, and the wild-type is shown in the upper panel.