Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency.

Antonino Montalbano,Lonny Juergensen,Ralph Roeth,Gudrun A Rappold,David Hassel,Gudrun Nuernberg,Tsutomu Ogata,Gerhard Binder,Eva Decker,Birgit Weiss,Maki Fukami,Susanne Fricke‐Otto

doi:10.15252/emmm.201606623

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.

Highlights

Mutations in the homeobox gene stature homeobox-containing (SHOX) cause SHOX deficiency, a condition with clinical manifestations ranging from short stature without dysmorphic signs to severe mesomelic skeletal dysplasia
Sanger sequencing identified a heterozygous variant, c.482T>C (p.Val161Ala), in the SHOX gene (NG_009385) in all individuals affected with Leri-Weill dyschondrosteosis (LWD). p.Val161 resides within the DNA binding domain (Fig 2A) and is highly conserved among SHOX vertebrate homologues
To determine the functional relevance of this variant, a luciferase assay in U2OS cells was carried out using the promoter of the fibroblast growth factor receptor 3 (FGFR3) gene, which is a known SHOX target (Decker et al, 2011)

Summary

Introduction

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. 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. Our findings describe CYP26C1 as the first genetic modifier for SHOX deficiency

Methods

Results

Conclusion