<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Identification and functional\r\ncharacterization of genetic modifiers for\r\nSHOX deficiency"^^ . "Human height is a complex trait with a high heritability. Mutations in the homeobox\r\ngene SHOX cause SHOX deficiency, the most frequent monogenic cause of\r\nshort stature. SHOX deficiency has high penetrance. However, the clinical severity\r\nof SHOX deficiency varies widely, ranging from short stature without dysmorphic\r\nsigns to mesomelic (disproportionate) skeletal dysplasia (Léri-Weill dyschondrosteosis,\r\nLWD) and different independent studies have reported rare SHOX deficiency\r\nindividuals presenting with normal height and no dysmorphic signs. To shed light\r\non the factors that modify disease severity/penetrance, we studied a three-generation\r\nfamily with five affected individuals presenting with LWD using whole genome linkage\r\nand whole exome sequencing analyses. By combining the data obtained with\r\nthese two independent methods, we found that the variant allele p.Phe508Cys of the\r\nretinoic acid catabolizing enzyme CYP26C1 co-segregated with the SHOX variant\r\nallele p.Val161Ala in the 5 affected individuals, while the SHOX mutant alone was\r\nalso present in 3 asymptomatic family members.\r\nScreening of a cohort of 68 LWD individuals led to the identification of two unrelated\r\nfamilies with SHOX deficiency bearing also additional damaging CYP26C1\r\nvariants in the more severely affected family members. These results support a role\r\nfor CYP26C1 in influencing the course of disease in SHOX deficiency patients.\r\nCYP26C1, similar to SHOX, is expressed in human primary chondrocytes and in\r\nzebrafish pectoral fins. Luciferase assays performed to functionally characterize the\r\nvariants identified in SHOX and CYP26C1 demonstrated their damaging effects on\r\ntheir activity: SHOX mutants were not able to transactivate the reporter gene expression,\r\nwhereas damaging variants in CYP26C1 affect its catabolic activity leading\r\nto increased levels of retinoic acid. High levels of retinoic acid significantly decreased\r\nSHOX expression in human primary chondrocytes and zebrafish embryos. Analysis\r\nof SHOX promoter unravelled an indirect effect of retinoic acid on SHOX expression.\r\nIndividual morpholino knockdown of either gene resulted in shortened pectoral fins\r\nin zebrafish embryos, which was more pronounced in SHOX. Depletion of both genes\r\nsimultaneously, aggravated the fin phenotype. Together our findings demonstrate\r\nthat SHOX and CYP26C1 act in a common molecular pathway (retinoic acid signaling)\r\ncontrolling limb growth and describe CYP26C1 as the first genetic modifier for\r\nSHOX-associated disease."^^ . "2017" . . . . . . . "Antonino"^^ . "Montalbano"^^ . "Antonino Montalbano"^^ . . . . . . "Identification and functional\r\ncharacterization of genetic modifiers for\r\nSHOX deficiency (Other)"^^ . . . . . . "Identification and functional\r\ncharacterization of genetic modifiers for\r\nSHOX deficiency (Other)"^^ . . . . . . "Identification and functional\r\ncharacterization of genetic modifiers for\r\nSHOX deficiency (Other)"^^ . . . . . . "Identification and functional\r\ncharacterization of genetic modifiers for\r\nSHOX deficiency (Other)"^^ . . . . . . "Identification and functional\r\ncharacterization of genetic modifiers for\r\nSHOX deficiency (Other)"^^ . . . . . . "Identification and functional\r\ncharacterization of genetic modifiers for\r\nSHOX deficiency (PDF)"^^ . . . "thesis_Antonino Montalbano.pdf"^^ . . "HTML Summary of #21940 \n\nIdentification and functional \ncharacterization of genetic modifiers for \nSHOX deficiency\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .