PUBLICATION
Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency
- Authors
- Montalbano, A., Juergensen, L., Roeth, R., Weiss, B., Fukami, M., Fricke-Otto, S., Binder, G., Ogata, T., Decker, E., Nuernberg, G., Hassel, D., Rappold, G.A.
- ID
- ZDB-PUB-161120-4
- Date
- 2016
- Source
- EMBO Molecular Medicine 8(12): 1455-1469 (Journal)
- Registered Authors
- Hassel, David
- Keywords
- clinical variability, genetic modifiers, limb development, retinoic acid, skeletal dysplasia
- MeSH Terms
-
- Cytochrome P450 Family 26/genetics*
- Cytochrome P450 Family 26/metabolism
- Aged
- Sequence Analysis, DNA
- Child
- Homeodomain Proteins/genetics*
- Male
- Zebrafish/anatomy & histology
- Adolescent
- Adult
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Young Adult
- Retinoic Acid 4-Hydroxylase/genetics
- Retinoic Acid 4-Hydroxylase/metabolism
- Female
- Osteochondrodysplasias/genetics*
- Osteochondrodysplasias/pathology*
- Humans
- Genetic Predisposition to Disease*
- Animals
- Tretinoin/metabolism
- Genetic Variation
- Gene Expression Profiling
- Growth Disorders/genetics*
- Growth Disorders/pathology*
- Severity of Illness Index
- Middle Aged
- PubMed
- 27861128 Full text @ EMBO Mol. Med.
Citation
Montalbano, A., Juergensen, L., Roeth, R., Weiss, B., Fukami, M., Fricke-Otto, S., Binder, G., Ogata, T., Decker, E., Nuernberg, G., Hassel, D., Rappold, G.A. (2016) Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency. EMBO Molecular Medicine. 8(12):1455-1469.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping