title: A novel 13 base pair insertion in the sonic hedgehog ZRS limb enhancer (ZRS/LMBR1) causes preaxial polydactyly with triphalangeal thumb.
abstract: 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.
authors.affiliation: Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Laurell
authors.forename: Julia E
authors.initials: JE
authors.lastname: Vandermeer
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Wenger
authors.forename: Giedre
authors.initials: G
authors.lastname: Grigelioniene
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordenskjöld
authors.forename: Marianne
authors.initials: M
authors.lastname: Arner
authors.forename: Anna Gerber
authors.initials: AG
authors.lastname: Ekblom
authors.forename: Gill
authors.initials: G
authors.lastname: Bejerano
authors.forename: Nadav
authors.initials: N
authors.lastname: Ahituv
authors.forename: Ann
authors.initials: A
authors.lastname: Nordgren
mesh_terms: D006228:Hand Deformities, Congenital / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D016254:Mutagenesis, Insertional / Q000276:immunology*; D017689:Polydactyly / Q000235:genetics*; D013933:Thumb / Q000473:pathology*
chemical_list: C485955:LMBR1 protein, human; D008565:Membrane Proteins