A novel 13 base pair insertion in the sonic hedgehog ZRS limb enhancer (ZRS/LMBR1) causes preaxial polydactyly with triphalangeal thumb

Authors

  • Tobias Laurell,

    Corresponding author
    1. Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
    2. Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
    3. Department of Hand Surgery, Södersjukhuset, Stockholm, Sweden
    • Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, 118 83, Stockholm, Sweden.
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    • These two authors contributed equally to this work.

  • Julia E. VanderMeer,

    1. Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California
    2. Institute for Human Genetics, University of California San Francisco, San Francisco, California
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    • These two authors contributed equally to this work.

  • Aaron M. Wenger,

    1. Department of Computer Science, Stanford University, Stanford, California
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  • Giedre Grigelioniene,

    1. Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
    2. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
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  • Agneta Nordenskjöld,

    1. Department of Women's and Children's Health and Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
    2. Department of Pediatric Surgery, Astrid Lindgren Children Hospital, Karolinska University Hospital, Stockholm, Sweden
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  • Marianne Arner,

    1. Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
    2. Department of Hand Surgery, Södersjukhuset, Stockholm, Sweden
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  • Anna Gerber Ekblom,

    1. Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
    2. Department of Hand Surgery, Södersjukhuset, Stockholm, Sweden
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  • Gill Bejerano,

    1. Department of Computer Science, Stanford University, Stanford, California
    2. Department of Developmental Biology, Stanford University, Stanford, California
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  • Nadav Ahituv,

    Corresponding author
    1. Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California
    2. Institute for Human Genetics, University of California San Francisco, San Francisco, California
    • Department of Bioengineering and Therapeutic Sciences, Institute for Human Genetics, University of California San Francisco, 513 Parnassus Avenue, Room HSE901H, Box 0794, San Francisco, California 94143, USA.
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  • Ann Nordgren

    1. Department of Molecular Medicine and Surgery and Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
    2. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
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  • Communicated by Sergio Ottolenghi

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. Hum Mutat 33:1063–1066, 2012. © 2012 Wiley Periodicals, Inc.

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