Impairment of SHOX nuclear localization as a cause for Léri-Weill syndrome

Nitin Sabherwal, Katja U. Schneider, Rüdiger J. Blaschke, Antonio Marchini, Gudrun Rappold

    Research output: Contribution to journalArticlepeer-review


    We report the characterization of the nuclear localization signal (NLS) of the short stature homeobox gene SHOX. Mutations within the SHOX gene cause Lαceri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LD) as well as idiopathic short stature (ISS). Furthermore, haploinsufficiency of SHOX has also been implicated in Turner syndrome. SHOX has been shown to be a cell-type-specific transcriptional activator that localizes to the nucleus. The SHOX protein contains a central homeodomain that together with its transactivation. domain regulates the transcription of its target sequences within the nucleus. The sequences for its nuclear localization have not been identified yet. Experimental characterization of SHOX-NLS by deletion mapping identified a non-classic type basic signal, AKCRK, in the recognition helix of the homeodomain. Fusion of this stretch of five amino acids to a cytoplasmic reporter protein resulted in its nuclear translocation. Functional analysis of a missense mutation R173C (C517T) affecting the identified SHOX-NLS in two families with LWS and LD showed that the mutated SHOX protein is unable to enter the nucleus. Conversely, we can demonstrate that insertion of the identified signal adjacent to the mutant site can restore its nuclear translocation. These results establish impairment of nuclear localization as a mechanistic basis for SHOX-related diseases.
    Original languageEnglish
    Pages (from-to)3041-3048
    Number of pages7
    JournalJournal of Cell Science
    Issue number14
    Publication statusPublished - 15 Jun 2004


    • Léri-Weill dyschondrosteosis (LWS)
    • Nuclear localization signal (NLS)
    • Red fluorescent protein (RFP)
    • Short stature homeobox gene (SHOX)


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