title: Impairment of SHOX nuclear localization as a cause for Léri-Weill syndrome.
abstract: We report the characterization of the nuclear localization signal (NLS) of the short stature homeobox gene SHOX. Mutations within the SHOX gene cause Léri-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.
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
authors.forename: Nitin
authors.initials: N
authors.lastname: Sabherwal
authors.forename: Katja U
authors.initials: KU
authors.lastname: Schneider
authors.forename: Rüdiger J
authors.initials: RJ
authors.lastname: Blaschke
authors.forename: Antonio
authors.initials: A
authors.lastname: Marchini
authors.forename: Gudrun
authors.initials: G
authors.lastname: Rappold
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D004252:DNA Mutational Analysis; D008040:Genetic Linkage; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals; D010009:Osteochondrodysplasias / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D000074122:Short Stature Homeobox Protein; D013577:Syndrome; D014424:Turner Syndrome / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D019913:Nuclear Localization Signals; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein