DETERMINATION OF THE GENOMIC STRUCTURE OF THE XNP ATRX GENE ENCODING A POTENTIAL ZINC-FINGER HELICASE/

The XNP/ATR-X gene is involved in several X-linked mental retardation phenotypes: the ATR-X syndrome, the Juberg-Marsidi syndrome, and some severe mental retardation phenotypes without a-thalassemia. Using a ve ctorette strategy, we have identified and sequenced the intron/exon bo undaries of this gene. The gene is composed of 35 exons. It encodes a potential protein of 2492 amino acids. A search of the databases ident ified three zinc finger motifs within the 5' end of the gene. Expressi on analysis in different tissues indicated that an alternative splicin g event that involves exon 6 is occurring, One of these alternatively spliced transcripts is predominantly expressed in embryonic tissues. T hese data led us to search for mutations in the 5' region in ATRX pati ents without other mutations in the 3' region. In one patient a mutati on was found in which part of exon 7 was removed from the XNP transcri pt, as a result of a mutation creating a novel splice site that is sub stituted for the natural splice site. This new splicing event removed one zinc finger motif. This is the first example of a mutation in XNP within the 5' coding region. It suggests that mutations will be predom inantly found in the helicase region as well as in the zinc finger reg ions and leads us to propose a large screening of additional patients. (C) 1997 Academic Press.