Identification of a novel gene, ETX1 from Xp21.1, a candidate gene for X-linked retintis 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. The gene, called EXT1, spans 80 kilobases and contains 12 exons, at least two of which are alternatively spliced and have predicted products of 464 and 471 amino acids respectively. Conceptual translation of the open reading frames shows one product with a 30 amino acid signal peptide, which is absent from the alternative transcript, followed by three complement control protein domains, a hydrophobic region with a possible role in membrane anchorage and short 17 amino acid putative cytoplasmic carboxyl terminus. An alternative first exon contains a 39 amino acid open reading frame which is rich in serine and threonine residues 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 within the region thought to contain the x-linked retinitis pigmentosa (xIRP) gene, RP3, it was screened for mutation within a set of 45 xIRP patients using single strand conformation analysis and/or chemical cleavage of mismatch using reverse transcription/polymerase chain reaction amplification of polyA+RNA from blood cells. Three low frequently variants (17-23Ldel, P225S, S413F) were found in both patients and controls; one of which (P225S) was found in four of 45 unrelated patient chromosomes and one of 178 control chromosomes (p <0.001). The allelic association between P225S and xIRP alleles suggests a common ancestral chromosome bearing the P225S variant and an RP3 mutation at a neighbouring locus.