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Presenting Author(s) Gudrun Rappold
Abstract Title Novel point mutations R173C and A170P in the SHOX homeodomain defines impaired nuclear translocation as a molecular cause for Léri-Weill dyschondrosteosis and Langer dysplasia.
Full author List N. Sabherwal 1, R.J. Blaschke 1, K.U. Schneider 1, A. Marchini 1, D. Heine-Suner 2, J. Rosell 2, W.F. Blum 3, G. Rappold 1
Text of abstract The short stature homeobox gene SHOX resides within the pseudoautosomal region of the sex chromosomes and encodes two isoforms of a paired-related homeodomain protein. SHOX haploinsufficiency leads to phenotypically heterogeneous short stature conditions including idiopathic short stature and Léri-Weill dyschondrosteosis and is involved in growth retardation and skeletal abnormalities in Turner syndrome. SHOX has been shown to encode a cell type specific transcriptional activator that localizes to the nucleus. Here we report the identification of the Nuclear Localization Signal (NLS) within the homeodomain of SHOX. Deletion mapping identified a non-classical type basic signal, AKCRK, in the recognition helix of the homeodomain. Fusion of this five amino acids stretch to a cytoplasmic reporter protein resulted in its nuclear translocation. During a large scale SHOX mutation analysis study, we identified two different mis-sense mutations, R173C (C517T) and A170P (G508C), within the identified SHOX-NLS in three families with Léri-Weill and Langer syndrome. Functional analysis of these missense mutations showed that the mutated SHOX protein carrying either of these mutations is unable to translocate to the nucleus. Conversely, we can demonstrate that insertion of the identified signal adjacent to the mutant site can restore its nuclear translocation. Our data explain Léri-Weill and Langer syndrome conditions on a molecular and cellular level and show that misregulation of subcellular localization contributes to clinically relevant phenotypes.
Which session is your work most relevant to: Human limb abnormalities