Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency
Abstract Mutations in the homeobox gene SHOX cause SHOX deficiency, a condition with clinical manifestations ranging from short stature without dysmorphic signs to severe mesomelic skeletal dysplasia. In rare cases, individuals with SHOX deficiency are asymptomatic. To elucidate the factors that mod...
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| Format: | Article |
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Springer Nature
2016-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201606623 |
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| author | Antonino Montalbano Lonny Juergensen Ralph Roeth Birgit Weiss Maki Fukami Susanne Fricke‐Otto Gerhard Binder Tsutomu Ogata Eva Decker Gudrun Nuernberg David Hassel Gudrun A Rappold |
| author_facet | Antonino Montalbano Lonny Juergensen Ralph Roeth Birgit Weiss Maki Fukami Susanne Fricke‐Otto Gerhard Binder Tsutomu Ogata Eva Decker Gudrun Nuernberg David Hassel Gudrun A Rappold |
| author_sort | Antonino Montalbano |
| collection | DOAJ |
| description | Abstract Mutations in the homeobox gene SHOX cause SHOX deficiency, a condition with clinical manifestations ranging from short stature without dysmorphic signs to severe mesomelic skeletal dysplasia. In rare cases, individuals with SHOX deficiency are asymptomatic. To elucidate the factors that modify disease severity/penetrance, we studied a three‐generation family with SHOX deficiency. The variant p.Phe508Cys of the retinoic acid catabolizing enzyme CYP26C1 co‐segregated with the SHOX variant p.Val161Ala in the affected individuals, while the SHOX mutant alone was present in asymptomatic individuals. Two further cases with SHOX deficiency and damaging CYP26C1 variants were identified in a cohort of 68 individuals with LWD. The identified CYP26C1 variants affected its catabolic activity, leading to an increased level of retinoic acid. High levels of retinoic acid significantly decrease SHOX expression in human primary chondrocytes and zebrafish embryos. Individual morpholino knockdown of either gene shortens the pectoral fins, whereas depletion of both genes leads to a more severe phenotype. Together, our findings describe CYP26C1 as the first genetic modifier for SHOX deficiency. |
| format | Article |
| id | doaj-art-58e159e9c09d4bc3a1633d55a5311edb |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-58e159e9c09d4bc3a1633d55a5311edb2025-08-20T03:42:52ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-11-018121455146910.15252/emmm.201606623Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiencyAntonino Montalbano0Lonny Juergensen1Ralph Roeth2Birgit Weiss3Maki Fukami4Susanne Fricke‐Otto5Gerhard Binder6Tsutomu Ogata7Eva Decker8Gudrun Nuernberg9David Hassel10Gudrun A Rappold11Department of Human Molecular Genetics, Heidelberg UniversityDepartment of Internal Medicine III ‐ Cardiology, Heidelberg University HospitalDepartment of Human Molecular Genetics, Heidelberg UniversityDepartment of Human Molecular Genetics, Heidelberg UniversityDepartment of Molecular Endocrinology, National Research Institute for Child Health and DevelopmentChildren's Hospital KrefeldChildren's Hospital, University of TübingenDepartment of Pediatrics, Hamamatsu University School of MedicineBioscientia Center for Human GeneticsCenter for Molecular MedicineDepartment of Internal Medicine III ‐ Cardiology, Heidelberg University HospitalDepartment of Human Molecular Genetics, Heidelberg UniversityAbstract Mutations in the homeobox gene SHOX cause SHOX deficiency, a condition with clinical manifestations ranging from short stature without dysmorphic signs to severe mesomelic skeletal dysplasia. In rare cases, individuals with SHOX deficiency are asymptomatic. To elucidate the factors that modify disease severity/penetrance, we studied a three‐generation family with SHOX deficiency. The variant p.Phe508Cys of the retinoic acid catabolizing enzyme CYP26C1 co‐segregated with the SHOX variant p.Val161Ala in the affected individuals, while the SHOX mutant alone was present in asymptomatic individuals. Two further cases with SHOX deficiency and damaging CYP26C1 variants were identified in a cohort of 68 individuals with LWD. The identified CYP26C1 variants affected its catabolic activity, leading to an increased level of retinoic acid. High levels of retinoic acid significantly decrease SHOX expression in human primary chondrocytes and zebrafish embryos. Individual morpholino knockdown of either gene shortens the pectoral fins, whereas depletion of both genes leads to a more severe phenotype. Together, our findings describe CYP26C1 as the first genetic modifier for SHOX deficiency.https://doi.org/10.15252/emmm.201606623clinical variabilitygenetic modifierslimb developmentretinoic acidskeletal dysplasia |
| spellingShingle | Antonino Montalbano Lonny Juergensen Ralph Roeth Birgit Weiss Maki Fukami Susanne Fricke‐Otto Gerhard Binder Tsutomu Ogata Eva Decker Gudrun Nuernberg David Hassel Gudrun A Rappold Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency EMBO Molecular Medicine clinical variability genetic modifiers limb development retinoic acid skeletal dysplasia |
| title | Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency |
| title_full | Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency |
| title_fullStr | Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency |
| title_full_unstemmed | Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency |
| title_short | Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency |
| title_sort | retinoic acid catabolizing enzyme cyp26c1 is a genetic modifier in shox deficiency |
| topic | clinical variability genetic modifiers limb development retinoic acid skeletal dysplasia |
| url | https://doi.org/10.15252/emmm.201606623 |
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