ESPE Abstracts (2018) 89 P-P1-175

Dual Function of the Retinoic Acid Catabolizing Enzyme CYP26C1 - Underlying Idiopathic Short Stature and Modifying Disease Severity in SHOX Deficiency

Antonino Montalbanoa, Lonny Juergensenb, Maki Fukamic, Christian T Thield, Nadine H Hauerd, Susanne Fricke-Ottoe, Gerhard Binderf, Y Naikig, Tsutomu Ogatah, David Hassela & Gudrun A Rappolda

aDepartment of Human Molecular Genetics – Institute of Human Genetics - Heidelberg University, Heidelberg, Germany; bDepartment of Internal Medicine III – Cardiology - Heidelberg University, Heidelberg, Germany; cDepartment of Molecular Endocrinology - National Research Institute for Child Health and Development, Tokyo, Japan; dInstitute of Human Genetics - Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; eChildren’s Hospital Krefeld, Krefeld, Germany; fChildren’s Hospital, University of Tübingen, Tübingen, Germany. gDivision of Endocrinology and Metabolism – National Center for Child Health and Development, Tokyo, Japan; hDepartment of Pediatrics - Hamamatsu University School of Medicine, Hamamatsu, Japan

Short stature is diagnosed when height is significantly below the average of the general population for that person’s age and sex. To elucidate the factors that modify disease severity/penetrance in short stature, we have studied a three-generation family with SHOX deficiency. We have found that the retinoic acid degrading enzyme CYP26C1 is a modifier for SHOX deficiency phenotypes towards the more severe clinical manifestations (Leri-Weill dyschondrosteosis) and confirmed these findings in independent cases. Here, we asked whether damaging variants in CYP26C1 alone could lead to short stature. We performed exome and Sanger sequencing to analyze 856 individuals with short stature where SHOX deficiency was previously excluded. Three different damaging missense variants and one splicing variant were identified in six independent individuals. The functional significance of the identified variants was tested in vitro (splicing defect) or in vivo (missense mutations) using Zebrafish as a model. The identified CYP26C1 variants affected the catabolic activity of CYP26C1 in human primary chondrocytes and zebrafish embryos. Together, the genetic and functional data reported here indicate that CYP26C1 represents a novel gene underlying growth disorders with dual function: damaging variants in CYP26C1 in the absence of SHOX mutations can lead to short stature and damaging variants in CYP26C1 modify SHOX deficiency phenotypic outcomes through the retinoic acid signaling pathway.