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.

A SHOX géndeletio előfordulása idiopáthiás alacsonynövésben. Multicentrikus tanulmány

“…A SHOX-eltérés okozta klinikai kép súlyossága változó, az egyéb tünetet alig mutató alacsonynövéstől a csontrendszer kifejezett érintettségével járó fenotípusig. A fenotípus heterogenitására utal az a megfigyelés is, hogy az azonos mutációval rendelkező családtagok kö-zött is nagy különbség lehet a klinikai jelek megléte, illetve súlyossága tekintetében [2,3].…”

Functional missense and splicing variants in the retinoic acid catabolizing enzyme CYP26C1 in idiopathic short stature

“…We have recently reported that CYP26C1 acts as a genetic modifier for SHOX deficiency [4]. Patients bearing damaging variants in both SHOX and CYP26C1 presented with more severe phenotypes when compared to family members carrying only SHOX variants.…”

“…Whole-mount in situ hybridization was performed as described previously [12]. Probes were designed and synthesized as previously described [4]. Images were taken with the microscope SZX16, Cell D Imaging Software (Olympus).…”

“…In a recent study, we identified CYP26C1 as a genetic modifier driving SHOX deficiency toward a more severe phenotype [4]. All the combined SHOX (MIM:312865) and CYP26C1 (MIM: 608428) variants were found so far in patients with Léri-Weill dyschondrosteosis (MIM:127300), the severe form of SHOX deficiency (MIM: 300582).…”

“…CYP26B1, another member of the CYP26 family, has been shown to be involved in skeleton development and, variants in this gene, lead to craniosynostosis and multiple skeletal anomalies including shorter limbs in humans [8]. Loss of cyp26c1 in zebrafish embryos leads to accumulation of RA resulting in reduction of SHOX expression and smaller limbs [4].…”