title: Alteration of DNA binding, dimerization, and nuclear translocation of SHOX homeodomain mutations identified in idiopathic short stature and Leri-Weill dyschondrosteosis.
abstract: Haploinsufficiency of the short stature homeobox gene SHOX has been found in patients with idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). In addition to complete gene deletions and nonsense mutations, several missense mutations have been identified in both patient groups, leading to amino acid substitutions in the SHOX protein. The majority of missense mutations were found to accumulate in the region encoding the highly conserved homeodomain of the paired-like type. In this report, we investigated nine different amino acid exchanges in the homeodomain of SHOX patients with ISS and LWD. We were able show that these mutations cause an alteration of the biological function of SHOX by loss of DNA binding, reduced dimerization ability, and/or impaired nuclear translocation. Additionally, one of the mutations (c.458G>T, p.R153L) is defective in transcriptional activation even though it is still able to bind to DNA, dimerize, and translocate to the nucleus. Thus, we demonstrate that single missense mutations in the homeodomain fundamentally impair SHOX key functions, thereby leading to the phenotype observed in patients with LWD and ISS.
authors.affiliation: Department of Molecular Human Genetics, University of Heidelberg, Germany.
authors.forename: Katja U
authors.initials: KU
authors.lastname: Schneider
authors.forename: Antonio
authors.initials: A
authors.lastname: Marchini
authors.forename: Nitin
authors.initials: N
authors.lastname: Sabherwal
authors.forename: Ralph
authors.initials: R
authors.lastname: Röth
authors.forename: Beate
authors.initials: B
authors.lastname: Niesler
authors.forename: Tiina
authors.initials: T
authors.lastname: Marttila
authors.forename: Rüdiger J
authors.initials: RJ
authors.lastname: Blaschke
authors.forename: Margaret
authors.initials: M
authors.lastname: Lawson
authors.forename: Miroslav
authors.initials: M
authors.lastname: Dumic
authors.forename: Gudrun
authors.initials: G
authors.lastname: Rappold
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D001827:Body Height / Q000235:genetics*; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D019281:Dimerization; D005801:Genes, Homeobox / Q000235:genetics; D006130:Growth Disorders / Q000235:genetics*; D018398:Homeodomain Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D000074122:Short Stature Homeobox Protein; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein; D014157:Transcription Factors; D004247:DNA