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Eur J Hum Genet. 2004 Feb;12(2):121-6.

Novel missense mutations in the TRPS1 transcription factor define the nuclear localization signal.

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Institut für Humangenetik, Universitätsklinikum, Hufelandstr 55, Essen D-45122, Germany.


Deletion or mutation of the TRPS1 gene leads to the tricho-rhino-phalangeal syndromes (TRPS). The gene encodes a zinc-finger transcription factor, which contains two regions with basic amino acids LRRRRG (NLS1) and RRRTRKR (NLS2) that resemble potential nuclear localization signals (NLSs). Here, we describe the identification of novel TRPS1 mutations in patients with TRPS type I (TRPS I) and provide, by reconstructing the mutant TRPS1 proteins and subcellular localization studies, evidence that only the RRRTRKR motif functions as a NLS. Two different mutations affect the last arginine residue of this motif. The exchanges of arginine to histidine, found in two unrelated patients with TRPS I, as well as the exchange of arginine to cysteine, found in another unrelated patient, prevent the translocation of the mutant TRPS1 to the nucleus when ectopically expressed in COS 7 cells. In contrast, a mutant that lacks the conserved GATA-type zinc-finger domain and most of the LRRRRG motif is able to enter the nucleus.

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