SLC29A3 mutation in a patient with syndromic diabetes with features of pigmented hypertrichotic dermatosis with insulin-dependent diabetes, H syndrome and Faisalabad histiocytosis.
Abstract Aims Atypical forms of diabetes may be caused by monogenic mutations in key genes controlling beta-cell development, survival and function. This report describes an insulin-dependent diabetes patient with a syndromic presentation in whom a homozygous SLC29A3 mutation was identified. Methods SLC29A3 was selected as the candidate gene based on the patient's clinical manifestations, and all exons and flanking regions in the patient's genomic DNA were sequenced. Results A homozygous splice mutation (c.300+1G>C) resulting in a frameshift and truncated protein (p.N101LfsX34) was identified. The patient had insulin-dependent diabetes, congenital deafness, short stature, hyperpigmented patches on the skin, dysmorphic features, cardiomegaly, arthrogryposis, hepatosplenomegaly, anaemia with erythroblastopenia, and an inflammatory syndrome with fever and arthritis; she also presented with a fibrotic mediastinal mass. These clinical features overlapped with pigmented hypertrichosis with insulin-dependent diabetes (PHID), H syndrome, Faisalabad histiocytosis and sinus histiocytosis with massive lymphadenopathy (SHML), all of which are also caused by SLC29A3 mutations. Conclusion This is the most severe case reported of SLC29A3 mutations with cumulative features of all these syndromes. This extreme severity coincides with the most N-terminal location of the truncation mutation, thereby affecting all alternative transcripts of the gene. This case report extends the clinical variability of homozygous SLC29A3 mutations that result in a spectrum of multisystemic manifestations.
The SLC29A3 gene, encoding hENT3, a member of the equilibrative nucleoside transporter family, has recently been found mutated in Faisalabad histiocytosis, pigmented hypertrichotic dermatosis with insulin-dependent diabetes, familial sinus histiocytosis with massive lymphadenopathy (SHML), and H syndromes. We here report clinical and genetic findings of an Egyptian family with H syndrome. We describe two siblings, a 19-yr old girl and a 15-yr old boy, of consanguineous parents. From 5 yr of age,...
#2James T. Lu(Human Genome Sequencing Center)H-Index: 23
Last. Brendan Lee(HHMI: Howard Hughes Medical Institute)H-Index: 83
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Dysosteosclerosis (DSS) is the form of osteopetrosis distinguished by the presence of skin findings such as red-violet macular atrophy, platyspondyly and metaphyseal osteosclerosis with relative radiolucency of widened diaphyses. At the histopathological level, there is a paucity of osteoclasts when the disease presents. In two patients with DSS, we identified homozygous or compound heterozygous missense mutations in SLC29A3 by whole-exome sequencing. This gene encodes a nucleoside transporter, ...
Diabetes mellitus diagnosed during the first 2 years of life differs from the disease in older children regarding its causes, clinical characteristics, treatment options and needs in terms of education and psychosocial support. Over the past decade, new genetic causes of neonatal diabetes mellitus have been elucidated, including monogenic β‑cell defects and chromosome 6q24 abnormalities. In patients with KCNJ11 or ABCC8 mutations and diabetes mellitus, oral sulfonylurea offers an easy and effect...
We investigated two siblings with granulomatous histiocytosis prominent in the nasal area, mimicking rhinoscleroma and Rosai-Dorfman syndrome. Genome-wide linkage analysis and whole-exome sequencing identified a homozygous frameshift deletion in SLC29A3, which encodes human equilibrative nucleoside transporter-3 (hENT3). Germline mutations in SLC29A3 have been reported in rare patients with a wide range of overlapping clinical features and inherited disorders including H syndrome, pigmented hype...
In 2008, SLC29A3 has been implicated in a syndromic form of genodermatosis: H syndrome. The major features encountered in H syndrome are Hearing loss, Hyperglycaemia, Heart anomalies, Hypertrichosis, Hyperpigmentation, Hepatomegaly and Hypogonadism. More recently, SLC29A3 mutations have been described in families presenting syndromes associating generalized histiocytosis to systemic progressive features: severe camptodactyly, hearing loss, hypogonadism, hepatomegaly, heart defects and skin hyper...
The H syndrome (OMIM 612391) is a recently described autosomal recessive disorder characterized by cutaneous hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, short stature (low height), hyperglycaemia/diabetes mellitus, hallux valgus, and fixed flexion contractures of the toe and finger joints.1,2 Histologically, there is an inflammatory infiltrate consisting mainly of histiocytes, later replaced by fibrosis of the deep dermis and subcutis.3 In ...
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 mappi...
#1Simon T. Cliffe(UNSW: University of New South Wales)H-Index: 6
#2Jamie M. Kramer(Radboud University Nijmegen Medical Centre)H-Index: 21
Last. Michael F. Buckley(Radboud University Nijmegen Medical Centre)H-Index: 22
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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 enco...
human equilibrative nucleoside transporter-3 (hENT3) was recently reported as a pH-dependent, intracellular (lysosomal) transporter capable of transporting anti-human immunodeficiency virus (HIV) dideoxynucleosides (ddNs). Because most anti-HIV ddNs (e.g., zidovudine, AZT) exhibit clinical mitochondrial toxicity, we investigated whether hENT3 facilitates transport of anti-HIV ddNs into the mitochondria. Cellular fractionation and immunofluorescence microscopy studies in several human cell lines ...
Background The association of cutaneous hyperpigmented, hypertrichotic, and indurated patches associated with hearing loss, short stature, cardiac anomalies, hepatosplenomegaly, scrotal masses, and hypogonadism has not, to our knowledge, been previously recognized as a disease entity. Objective We describe 10 patients with the above-mentioned findings. Methods Patients were clinically examined and extensive laboratory evaluation was performed. Results We describe 10 patients from 6 Arab consangu...
BACKGROUND: H syndrome (HS) is a rare autoinflammatory disease caused by a mutation in the solute carrier family 29, member 3 (SCL29A3) gene. It has a variable clinical presentation and little phenotype-genotype correlation. The pathognomonic sign of HS is cutaneous hyperpigmentation located mainly in the inner thighs and often accompanied by other systemic manifestations. Improvement after tocilizumab treatment has been reported in a few patients with HS. We report the first patient with HS who...
A Moroccan 19-year-old patient, from a non-consanguineous marriage, with a history of diabetes mellitus since the age of 8 years, presented at the age of 14 year with hypertrichosis and hyperpigmentation on the upper inner thighs, with involvement of the genitalia, trunk and limbs. The physical
Mutations in human equilibrative nucleoside transporter 3 (ENT3) encoded by SLC29A3 results in anemia and erythroid hypoplasia, suggesting that ENT3 may regulate erythropoiesis. Here, we demonstrate that lysosomal ENT3 transport of taurine-conjugated bile acids (TBA) facilitates TBA chemical chaperone function and alleviates endoplasmic reticulum (ER) stress in expanding mouse hematopoietic stem and progenitor cells (HSPCs). Slc29a3−/− HSPCs accumulate less TBA despite elevated levels of TBA in ...
#2Naz Surucu(METU: Middle East Technical University)H-Index: 2
Last. Ilhan Tezcan(Hacettepe University)H-Index: 36
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Abstract Introduction H Syndrome is an autosomal recessive (AR) disease caused by defects in SLCA29A3 gene. This gene encodes the equilibrative nucleoside transporter, the protein which is highly expressed in spleen, lymph node and bone marrow. Autoinflammation and autoimmunity accompanies H Syndrome (HS). Aim The aim was to further elucidate the mechanisms of disease by molecular studies in a patient with SLC29A3 gene defect. Patient and Methods Mitochondrial dysfunction, lysosomal integrity, c...
Mutations exclusively in equilibrative nucleoside transporter 3 (ENT3), the only intracellular nucleoside transporter within the solute carrier 29 (SLC29) gene family, cause an expanding spectrum of human genetic disorders (e.g., H syndrome, PHID syndrome, and SHML/RDD syndrome). Here, we identify adult stem cell deficits that drive ENT3-related abnormalities in mice. ENT3 deficiency alters hematopoietic and mesenchymal stem cell fates; the former leads to stem cell exhaustion, and the latter le...
: Background H syndrome ([OMIM] 602782) is an autosomal recessive disorder with systemic manifestations and characteristic skin lesions, caused by mutations of the SLC29A3 gene. Short stature and diabetes mellitus are the major endocrine problems related to H syndrome, however, clear data from clinical follow-up of H syndrome patients is lacking in the literature. Case presentation Here, we present follow-up of a Turkish girl diagnosed with H syndrome at the age of 10 with a homozygous 310(c.933...
Background H Syndrome is an autosomal recessive disorder characterized by cutaneous hyperpigmentation, hypertrichosis, and induration with numerous systemic manifestations. The syndrome is caused by mutations in SLC29A3, a gene located on chromosome 10q23, which encodes the human equilibrative transporter 3 (hENT3). Less than 100 patients with H syndrome have been described in the literature, with the majority being of Arab descent, and only a few from North America.
Abstract Equilibrative nucleoside transporters (ENTs) translocate hydrophilic nucleosides across cellular membranes and are essential for salvage nucleotide synthesis and purinergic signaling. Unlike the prototypic human ENT members hENT1 and hENT2, which mediate plasma membrane nucleoside transport at pH 7.4, hENT3 is an acidic pH-activated lysosomal transporter partially localized to mitochondria. Recent studies demonstrate that hENT3 is indispensable for lysosomal homeostasis, and that mutati...
H syndrome is an autosomal recessive syndrome, which affects the skin and some vital organs, it is caused by mutations in the SLC29A3 gene, encoding the human equilibrative nucleoside transporter hENT3. This report describes a patient with typical features of H syndrome. Based on the patient's clinical features, SLC29A3 was selected for molecular investigation. Through direct sequencing, a compound heterozygous alteration in the SLC29A3 gene was found. The c.243delA frameshift mutation leading t...