Universität zu Köln

Li, Yun, Laue, Kathrin, Temtamy, Samia, Aglan, Mona, Kotan, L. Damla, Yigit, Goekhan, Canan, Husniye, Pawlik, Barbara, Nuernberg, Gudrun, Wakeling, Emma L., Quarrell, Oliver W., Baessmann, Ingelore, Lanktree, Matthew B., Yilmaz, Mustafa, Hegele, Robert A., Amr, Khalda ORCID: 0000-0001-8472-5911, May, Klaus W., Nuernberg, Peter, Topaloglu, A. Kemal, Hammerschmidt, Matthias and Wollnik, Bernd (2010). Temtamy Preaxial Brachydactyly Syndrome Is Caused by Loss-of-Function Mutations in Chondroitin Synthase 1, a Potential Target of BMP Signaling. Am. J. Hum. Genet., 87 (6). S. 757 - 768. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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Abstract

Altered Bone Morphogenetic Protein (BMP) signaling leads to multiple developmental defects, including brachydactyly and deafness. Here we identify chondroitin synthase 1 (CHSY1) as a potential mediator of BMP effects. We show that loss of human CHSY1 function causes autosomal-recessive Temtamy preaxial brachydactyly syndrome (ITBS), mainly characterized by limb malformations, short stature, and hearing loss. After mapping the TITS locus to chromosome 15q26-qterm, we identified causative mutations in five consanguineous TPBS families. In zebrafish, antisense-mediated chsy1 knockdown causes defects in multiple developmental processes, some of which are likely to also be causative in the etiology of TPBS. In the inner ears of zebrafish larvae, chsy1 is expressed similarly to the BMP inhibitor don and in a complementary fashion to bmp2b. Furthermore, unrestricted Bmp2b signaling or loss of Dan activity leads to reduced chsy1 expression and, during epithelial morphogenesis, defects similar to those that occur upon Chsy1 inactivation, indicating that Bmp signaling affects inner-ear development by repressing chsy1. In addition, we obtained strikingly similar zebrafish phenotypes after chsy1 overexpression, which might explain why, in humans, brachydactyly can be caused by mutations leading either to loss or to gain of BMP signaling.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Li, Yun UNSPECIFIED UNSPECIFIED UNSPECIFIED Laue, Kathrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Temtamy, Samia UNSPECIFIED UNSPECIFIED UNSPECIFIED Aglan, Mona UNSPECIFIED UNSPECIFIED UNSPECIFIED Kotan, L. Damla UNSPECIFIED UNSPECIFIED UNSPECIFIED Yigit, Goekhan UNSPECIFIED UNSPECIFIED UNSPECIFIED Canan, Husniye UNSPECIFIED UNSPECIFIED UNSPECIFIED Pawlik, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Gudrun UNSPECIFIED UNSPECIFIED UNSPECIFIED Wakeling, Emma L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Quarrell, Oliver W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Baessmann, Ingelore UNSPECIFIED UNSPECIFIED UNSPECIFIED Lanktree, Matthew B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yilmaz, Mustafa UNSPECIFIED UNSPECIFIED UNSPECIFIED Hegele, Robert A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Amr, Khalda UNSPECIFIED orcid.org/0000-0001-8472-5911 UNSPECIFIED May, Klaus W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Topaloglu, A. Kemal UNSPECIFIED UNSPECIFIED UNSPECIFIED Hammerschmidt, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Wollnik, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-490743
DOI:	10.1016/j.ajhg.2010.10.003
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	87
Number:	6
Page Range:	S. 757 - 768
Date:	2010
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ZEBRAFISH INNER-EAR; LINKAGE ANALYSIS; LATERAL-LINE; EXPRESSION; MORPHOGENESIS; HYPERPHALANGISM; DEAFNESS; DISEASE; SULFATE; EMBRYO Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/49074