These two authors contributed equally to this work.
A novel 13 base pair insertion in the sonic hedgehog ZRS limb enhancer (ZRS/LMBR1) causes preaxial polydactyly with triphalangeal thumb†
Article first published online: 11 MAY 2012
© 2012 Wiley Periodicals, Inc.
Volume 33, Issue 7, pages 1063–1066, July 2012
How to Cite
Laurell, T., VanderMeer, J. E., Wenger, A. M., Grigelioniene, G., Nordenskjöld, A., Arner, M., Ekblom, A. G., Bejerano, G., Ahituv, N. and Nordgren, A. (2012), A novel 13 base pair insertion in the sonic hedgehog ZRS limb enhancer (ZRS/LMBR1) causes preaxial polydactyly with triphalangeal thumb. Hum. Mutat., 33: 1063–1066. doi: 10.1002/humu.22097
Communicated by Sergio Ottolenghi
- Issue published online: 5 JUN 2012
- Article first published online: 11 MAY 2012
- Accepted manuscript online: 11 APR 2012 04:24PM EST
- Manuscript Accepted: 16 MAR 2012
- Manuscript Received: 26 MAY 2011
- Swedish Research Council; the Swedish Society of Medicine; Foundation Frimurarna Barnhuset in Stockholm; Sällskapet Barnavård; HRH the Crown Princess Lovisa Foundation; Karolinska Institutet; Stockholm City Council
- NICHD. Grant Number: R01HD059862 (to N.A., G.B., and J.E.V.)
- a Stanford Graduate Fellowship (to A.M.W.); Bio-X Stanford Interdisciplinary Graduate Fellowship (to A.M.W.); the Packard foundation (to G.B.)
- NHGRI. Grant Number: R01HG005058 (N.A. with G.B.)
- NIGMS. Grant Number: GM61390 (N.A.)
- NSF Center for Science of Information (CSoI). Grant Number: CCF-0939370 (G.B.)
Mutations in the Sonic hedgehog limb enhancer, the zone of polarizing activity regulatory sequence (ZRS, located within the gene LMBR1), commonly called the ZRS), cause limb malformations. In humans, three classes of mutations have been proposed based on the limb phenotype; single base changes throughout the region cause preaxial polydactyly (PPD), single base changes at one specific site cause Werner mesomelic syndrome, and large duplications cause polysyndactyly. This study presents a novel mutation—a small insertion. In a Swedish family with autosomal-dominant PPD, we found a 13 base pair insertion within the ZRS, NG_009240.1:g.106934_106935insTAAGGAAGTGATT (traditional nomenclature: ZRS603ins13). Computational transcription factor-binding site predictions suggest that this insertion creates new binding sites and a mouse enhancer assay shows that this insertion causes ectopic gene expression. This study is the first to discover a small insertion in an enhancer that causes a human limb malformation and suggests a potential mechanism that could explain the ectopic expression caused by this mutation. Hum Mutat 33:1063–1066, 2012. © 2012 Wiley Periodicals, Inc.