Human Molecular Genetics, 2003, Vol. 12, No. 10 1121-1130
DOI: 10.1093/hmg/ddg130
© 2003 Oxford University Press
Functional polymorphisms in the paternally expressed XL
s and its cofactor ALEX decrease their mutual interaction and enhance receptor-mediated cAMP formation
1Center of Molecular and Vascular Biology and 2Department of Pediatrics, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium
Received December 19, 2002; Revised February 21, 2003; Accepted March 17, 2003
The paternally expressed extra-large stimulatory G protein gene (XL
s) is a splice variant of the stimulatory G-protein gene (Gs) consisting of XL-exon1 and exons 2–13 of Gs. A second open reading frame (ORF) in XL-exon1, that completely overlaps the XL-domain ORF, encodes ALEX, which is translated from the XLs mRNA and binds the XL-domain of XLs. We previously demonstrated that a paternally inherited functional polymorphism in XL-exon1, consisting of a 36 bp insertion and two nucleotide substitutions, is associated with Gs hyperfunction in platelets, leading to an increased trauma-related bleeding tendency and is accompanied by neurological problems and brachydactyly in two families. Here, we describe eight additional patients with brachydactyly, who inherited the same XLs polymorphism paternally and who show Gs hyperfunction in their platelets and fibroblasts. All carriers also have an elongated ALEX protein, as a consequence of the paternally inherited insertion. The in vitro interaction between the two elongated XLs and ALEX proteins is markedly reduced. Moreover, XLs or ALEX can be co-immunoprecipitated with an antibody against either ALEX or XLs in platelets from a control but hardly from patients with the XLs/ALEX insertion. In contrast to the strong interaction between the two wild-type proteins, we suggest that this defective association results in unimpeded receptor-stimulated activation of XLs. The paternally inherited double XLs/ALEX functional polymorphism is also associated with elevated platelet membrane Gs protein levels. Both phenomena contribute to increased Gs signaling in patients with platelet hypersensitivity towards Gs-agonists and may be accompanied by neurological problems or growth deficiency.
* To whom correspondence should be addressed at: Center for Molecular and Vascular Biology, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium. Tel: +32 16345775; Fax: +32 16345990; Email: christel.vangeet{at}uz.kuleuven.ac.be
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