title: 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 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.
authors.affiliation: Department of Human Molecular Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Antonino
authors.initials: A
authors.lastname: Montalbano
authors.affiliation: Department of Internal Medicine III - Cardiology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Lonny
authors.initials: L
authors.lastname: Juergensen
authors.affiliation: Department of Human Molecular Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Roeth
authors.affiliation: Department of Human Molecular Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Weiss
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
authors.affiliation: Children's Hospital Krefeld, Krefeld, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Fricke-Otto
authors.affiliation: Children's Hospital, University of Tübingen, Tübingen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Binder
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
authors.affiliation: Bioscientia Center for Human Genetics, Ingelheim, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Decker
authors.affiliation: Center for Molecular Medicine, Cologne, Germany.|Cologne Center for Genomics, Cologne, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nuernberg
authors.affiliation: Department of Internal Medicine III - Cardiology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Hassel
authors.affiliation: Department of Human Molecular Genetics, Heidelberg University, Heidelberg, Germany gudrun.rappold@med.uni-heidelberg.de.|Interdisciplinary Centre for Neurosciences (IZN), University of Heidelberg, Heidelberg, Germany.
authors.forename: Gudrun A
authors.identifier: 0000-0002-3126-1508
authors.initials: GA
authors.lastname: Rappold
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D000072500:Cytochrome P450 Family 26 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006130:Growth Disorders / Q000235:genetics* / Q000473:pathology*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000473:pathology*; D000072516:Retinoic Acid 4-Hydroxylase / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D012720:Severity of Illness Index; D000074122:Short Stature Homeobox Protein; D014212:Tretinoin / Q000378:metabolism; D055815:Young Adult; D015027:Zebrafish / Q000033:anatomy & histology; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein; D029961:Zebrafish Proteins; D014212:Tretinoin; C482075:CYP26C1 protein, human; C000607084:Cyp26c1 protein, zebrafish; D000072500:Cytochrome P450 Family 26; D000072516:Retinoic Acid 4-Hydroxylase
keywords: clinical variability; genetic modifiers; limb development; retinoic acid; skeletal dysplasia