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A novel 13 base pair insertion in the sonic hedgehog ZRS limb enhancer (ZRS/ LMBR1 ) causes preaxial polydactyly with triphalangeal thumb
Author(s) -
Laurell Tobias,
VanderMeer Julia E.,
Wenger Aaron M.,
Grigelioniene Giedre,
Nordenskjöld Agneta,
Arner Marianne,
Ekblom Anna Gerber,
Bejerano Gill,
Ahituv Nadav,
Nordgren Ann
Publication year - 2012
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22097
Subject(s) - enhancer , biology , polydactyly , zone of polarizing activity , limb development , genetics , limb bud , sonic hedgehog , ectopic expression , transcription factor , gene , ectoderm , embryogenesis
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.