New mutations in XNP/ATR-X gene: a further contribution to genotype/phenotype relationship in ATR/X syndrome.

The molecular causes of ATR-X syndrome reside in mutations involving the XNP/ATR-X gene, which maps in the Xq13.3 region. Mutational analysis of this gene in two unrelated affected patients allowed us to identify two new molecular defects in two distinct regions of the gene. The first is a A-->G splice mutation in the acceptor site of the intron 11 that removes most of the 3' part of the protein, including the helicase domains and the glutamic acid stretch. Three cryptic acceptor splice sites are activated by this point mutation with consequent production of three types of abnormal mRNA: two with intronic insertions and a smaller one, approximately 10% of the total transcript, which is shorter than normal mRNA by one amino acid residue (E). Since the physiopathological characteristics of the patient carrying the splice mutation do not exhibit severe urogential abnormalities despite the lack of the -COOH end of the protein, a residual function of this third transcript is to be suspected. The second encountered nucleotide change (G-->T) leads to an R246L amino acid substitution in the putative zinc finger DNA-binding domain in the -NH2 terminal part of the protein.