IDENTIFICATION OF A NOVEL GENE, ETX1, FROM XP21.1, A CANDIDATE GENE FOR X-LINKED RETINITIS-PIGMENTOSA (RP3)

A novel gene encoding a 2.2 kilobase transcript has been isolated from the Xp21.1 region of the human X chromosome by exon amplification. Th e gene, called ETX1, spans 80 kilobases and contains 12 exons, at (eas t two of which are alternatively spliced and have predicted products o f 464 and 471 amino acids respectively. Conceptual translation of the open reading frames shows one product with a 30 amino acid signal pept ide, which is absent from the alternative transcript, followed by thre e complement control protein domains, a hydrophobic region with a poss ible role in membrane anchorage and a short 17 amino acid putative cyt oplasmic carboxyl terminus, An alternative first exon contains a 39 am ino acid open reading frame which is rich in serine and threonine resi dues and contains a potential chondroitin/dermatan sulphate attachment site, Northern analysis showed ETX1 expression within the retina and heart with lower levels in several other tissues, Since ETX1 lies with in the region thought to contain the X-linked retinitis pigmentosa (xI RP) gene, RP3, it was screened for mutation within a set of 45 xIRP pa tients using single strand conformation analysis and/or chemical cleav age of mismatch using reverse transcription/polymerase chain reaction amplification of polyA(+) RNA from blood cells. Three low frequency va riants (17-23Ldel, P225S, S413F) were found in both patients and contr ols; one of which (P225S) was found in four of 45 unrelated patient ch romosomes and one of 178 control chromosomes (p <0.001). The allelic a ssociation between P225S and xIRP alleles suggests a common ancestral chromosome bearing the P225S variant and an RP3 mutation at a neighbou ring locus.