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:
CreatorsEmailORCIDORCID Put Code
Li, YunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Laue, KathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Temtamy, SamiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aglan, MonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kotan, L. DamlaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yigit, GoekhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Canan, HusniyeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pawlik, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, GudrunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wakeling, Emma L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Quarrell, Oliver W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baessmann, IngeloreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lanktree, Matthew B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yilmaz, MustafaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hegele, Robert A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amr, KhaldaUNSPECIFIEDorcid.org/0000-0001-8472-5911UNSPECIFIED
May, Klaus W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Topaloglu, A. KemalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hammerschmidt, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
ZEBRAFISH INNER-EAR; LINKAGE ANALYSIS; LATERAL-LINE; EXPRESSION; MORPHOGENESIS; HYPERPHALANGISM; DEAFNESS; DISEASE; SULFATE; EMBRYOMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/49074

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