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Identification of a novel mutation in solute carrier family 29, member 3 in a Chinese patient with H syndrome.

ABSTRACT: H syndrome (OMIM 612391) is a recently described autosomal recessive genodermatosis characterized by indurated hyperpigmented and hypertrichotic skin, as well as other systemic manifestations. Most of the cases occurred in the Middle East areas or nearby countries such as Spain or India. The syndrome is caused by mutations in solute carrier family 29, member 3 (SLC29A3), the gene encoding equilibrative nucleoside transporter 3. The aim of this study was to identify pathogenic SLC29A3 mutations in a Chinese patient clinically diagnosed with H syndrome.Peripheral blood samples were collected from the patient and his parents. Genomic DNA was isolated by the standard method. All six SLC29A3 exons and their flanking intronic sequences were polymerase chain reaction (PCR)-amplified and the PCR products were subjected to direct sequencing.The patient, an 18-year-old man born to a nonconsanguineous Chinese couple, had more extensive cutaneous lesions, involving both buttocks and knee. In his genomic DNA, we identified a novel homozygous insertion-deletion, c. 1269_1270delinsA, in SLC29A3. Both of his parents were carriers of the mutation.We have identified a pathogenic mutation in a Chinese patient with H syndrome.

SUBMITTER: Liu JW

PROVIDER: S-EPMC4830313 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Identification of a novel mutation in solute carrier family 29, member 3 in a Chinese patient with H syndrome.

Liu Jia-Wei JW Si Nuo N Wang Lian-Qing LQ Shen Ti T Zeng Xue-Jun XJ Zhang Xue X Ma Dong-Lai DL

Chinese medical journal 20150501 10

<h4>Background</h4>H syndrome (OMIM 612391) is a recently described autosomal recessive genodermatosis characterized by indurated hyperpigmented and hypertrichotic skin, as well as other systemic manifestations. Most of the cases occurred in the Middle East areas or nearby countries such as Spain or India. The syndrome is caused by mutations in solute carrier family 29, member 3 (SLC29A3), the gene encoding equilibrative nucleoside transporter 3. The aim of this study was to identify pathogenic ...[more]

PMID: 25963354

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Project description:BackgroundHydrallantois is the excessive accumulation of fluid within the allantoic cavity in pregnant animals and is associated with fetal mortality. Although the incidence of hydrallantois is very low in artificial insemination breeding programs in cattle, recently 38 cows with the phenotypic appearance of hydrallantois were reported in a local subpopulation of Japanese Black cattle. Of these, 33 were traced back to the same sire; however, both their parents were reported healthy, suggesting that hydrallantois is a recessive inherited disorder. To identify autozygous chromosome segments shared by individuals with hydrallantois and the causative mutation in Japanese Black cattle, we performed autozygosity mapping using single-nucleotide polymorphism (SNP) array and exome sequencing.ResultsShared haplotypes of the affected fetuses spanned 3.52 Mb on bovine chromosome 10. Exome sequencing identified a SNP (g.62382825G > A, p.Pro372Leu) in exon 10 of solute carrier family 12, member 1 (SLC12A1), the genotype of which was compatible with recessive inheritance. SLC12A1 serves as a reabsorption molecule of Na(+)-K(+)-2Cl(-) in the apical membrane of the thick ascending limb of the loop of Henle in the kidney. We observed that the concentration of Na(+)-Cl(-) increased in allantoic fluid of homozygous SLC12A1 (g.62382825G > A) in a hydrallantois individual. In addition, SLC12A1-positive signals were localized at the apical membrane in the kidneys of unaffected fetuses, whereas they were absent from the apical membrane in the kidneys of affected fetuses. These results suggested that p.Pro372Leu affects the membrane localization of SLC12A1, and in turn, may impair its transporter activity. Surveillance of the risk-allele frequency revealed that the carriers were restricted to the local subpopulation of Japanese Black cattle. Moreover, we identified a founder individual that carried the mutation (g.62382825G > A).ConclusionsIn this study, we mapped the shared haplotypes of affected fetuses using autozygosity mapping and identified a de novo mutation in the SLC12A1 gene that was associated with hydrallantois in Japanese Black cattle. In kidneys of hydrallantois-affected fetuses, the mutation in SLC12A1 impaired the apical membrane localization of SLC12A1 and reabsorption of Na(+)-K(+)-2Cl(-) in the thick ascending limb of the loop of Henle, leading to a defect in the concentration of urine via the countercurrent mechanism. Consequently, the affected fetuses exhibited polyuria that accumulated in the allantoic cavity. Surveillance of the risk-allele frequency indicated that carriers were not widespread throughout the Japanese Black cattle population. Moreover, we identified the founder individual, and thus could effectively manage the disorder in the population.

Project description:Solute carrier family 7 member 2 (SLC7A2, also known as CAT2) is an inducible transporter of the semi-essential amino acid L-arginine (L-Arg), which has been implicated in wound repair. We have reported that both SLC7A2 expression and L-Arg availability are decreased in colonic tissues from inflammatory bowel disease patients and that mice lacking Slc7a2 exhibit a more severe disease course when exposed to dextran sulfate sodium (DSS) compared to wild-type (WT) mice. Here, we present evidence that SLC7A2 plays a role in modulating colon tumorigenesis in the azoxymethane (AOM)-DSS model of colitis-associated carcinogenesis (CAC). SLC7A2 was localized predominantly to colonic epithelial cells in WT mice. Utilizing the AOM-DSS model, Slc7a2-/- mice had significantly increased tumor number, burden, and risk of high-grade dysplasia vs. WT mice. Tumors from Slc7a2-/- mice exhibited significantly increased levels of the proinflammatory cytokines/chemokines IL-1β, CXCL1, CXCL5, IL-3, CXCL2, CCL3, and CCL4, but decreased levels of IL-4, CXCL9, and CXCL10 compared to tumors from WT mice. This was accompanied by a shift toward pro-tumorigenic M2 macrophage activation in Slc7a2-deficient mice, as marked by increased colonic CD11b+F4/80+ARG1+ cells with no alteration in CD11b+F4/80+NOS2+ cells by flow cytometry and immunofluorescence microscopy. The shift toward M2 macrophage activation was confirmed in bone marrow-derived macrophages from Slc7a2-/- mice. In bone marrow chimeras between Slc7a2-/- and WT mice, the recipient genotype drove the CAC phenotype, suggesting the importance of epithelial SLC7A2 in abrogating neoplastic risk. These data reveal that SLC7A2 has a significant role in the protection from CAC in the setting of chronic colitis, and suggest that the decreased SLC7A2 in inflammatory bowel disease (IBD) may contribute to CAC risk. Strategies to enhance L-Arg availability by supplementing L-Arg and/or increasing L-Arg uptake could represent a therapeutic approach in IBD to reduce the substantial long-term risk of colorectal carcinoma.

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Dataset Information

Identification of a novel mutation in solute carrier family 29, member 3 in a Chinese patient with H syndrome.

Publications

Identification of a novel mutation in solute carrier family 29, member 3 in a Chinese patient with H syndrome.

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