Universität zu Köln

Montalbano, Antonino, Juergensen, Lonny, Roeth, Ralph, Weiss, Birgit, Fukami, Maki ORCID: 0000-0001-9971-4035, Fricke-Otto, Susanne, Binder, Gerhard, Ogata, Tsutomu ORCID: 0000-0001-7178-9991, Decker, Eva, Nuernberg, Gudrun, Hassel, David and Rappold, Gudrun A. (2016). Retinoic acid catabolizing enzyme CYP26C1 is a genetic modifier in SHOX deficiency. EMBO Mol. Med., 8 (12). S. 1455 - 1470. HOBOKEN: WILEY. ISSN 1757-4684

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Montalbano, Antonino UNSPECIFIED UNSPECIFIED UNSPECIFIED Juergensen, Lonny UNSPECIFIED UNSPECIFIED UNSPECIFIED Roeth, Ralph UNSPECIFIED UNSPECIFIED UNSPECIFIED Weiss, Birgit UNSPECIFIED UNSPECIFIED UNSPECIFIED Fukami, Maki UNSPECIFIED orcid.org/0000-0001-9971-4035 UNSPECIFIED Fricke-Otto, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Binder, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Ogata, Tsutomu UNSPECIFIED orcid.org/0000-0001-7178-9991 UNSPECIFIED Decker, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Gudrun UNSPECIFIED UNSPECIFIED UNSPECIFIED Hassel, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Rappold, Gudrun A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-254157
DOI:	10.15252/emmm.201606623
Journal or Publication Title:	EMBO Mol. Med.
Volume:	8
Number:	12
Page Range:	S. 1455 - 1470
Date:	2016
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1757-4684
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language IDIOPATHIC SHORT STATURE; MUTATIONS; IDENTIFICATION; EXPRESSION; HOMEOBOX; REVEALS; GROWTH; HINDBRAIN; DELETION; PATTERN Multiple languages Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25415