%0 Generic
%A Montalbano, Antonino
%C Heidelberg, DE
%D 2017
%F heidok:21940
%R 10.11588/heidok.00021940
%T Identification and functional  characterization of genetic modifiers for  SHOX deficiency
%U https://archiv.ub.uni-heidelberg.de/volltextserver/21940/
%X Human height is a complex trait with a high heritability. Mutations in the homeobox  gene SHOX cause SHOX deficiency, the most frequent monogenic cause of  short stature. SHOX deficiency has high penetrance. However, the clinical severity  of SHOX deficiency varies widely, ranging from short stature without dysmorphic  signs to mesomelic (disproportionate) skeletal dysplasia (Léri-Weill dyschondrosteosis,  LWD) and different independent studies have reported rare SHOX deficiency  individuals presenting with normal height and no dysmorphic signs. To shed light  on the factors that modify disease severity/penetrance, we studied a three-generation  family with five affected individuals presenting with LWD using whole genome linkage  and whole exome sequencing analyses. By combining the data obtained with  these two independent methods, we found that the variant allele p.Phe508Cys of the  retinoic acid catabolizing enzyme CYP26C1 co-segregated with the SHOX variant  allele p.Val161Ala in the 5 affected individuals, while the SHOX mutant alone was  also present in 3 asymptomatic family members.  Screening of a cohort of 68 LWD individuals led to the identification of two unrelated  families with SHOX deficiency bearing also additional damaging CYP26C1  variants in the more severely affected family members. These results support a role  for CYP26C1 in influencing the course of disease in SHOX deficiency patients.  CYP26C1, similar to SHOX, is expressed in human primary chondrocytes and in  zebrafish pectoral fins. Luciferase assays performed to functionally characterize the  variants identified in SHOX and CYP26C1 demonstrated their damaging effects on  their activity: SHOX mutants were not able to transactivate the reporter gene expression,  whereas damaging variants in CYP26C1 affect its catabolic activity leading  to increased levels of retinoic acid. High levels of retinoic acid significantly decreased  SHOX expression in human primary chondrocytes and zebrafish embryos. Analysis  of SHOX promoter unravelled an indirect effect of retinoic acid on SHOX expression.  Individual morpholino knockdown of either gene resulted in shortened pectoral fins  in zebrafish embryos, which was more pronounced in SHOX. Depletion of both genes  simultaneously, aggravated the fin phenotype. Together our findings demonstrate  that SHOX and CYP26C1 act in a common molecular pathway (retinoic acid signaling)  controlling limb growth and describe CYP26C1 as the first genetic modifier for  SHOX-associated disease.