SPLICING MUTATION IN THE ATR-X GENE CAN LEAD TO A DYSMORPHIC MENTAL-RETARDATION PHENOTYPE WITHOUT ALPHA-THALASSEMIA

We have previously reported the isolation of a gene from Xq13 that cod es for a putative regulator of transcription (XNP) and has now been sh own to be the gene involved in the X-linked alpha-thalassemia with men tal retardation (ATR-X) syndrome. The widespread expression and numero us domains present in the putative protein suggest that this gene coul d be involved in other phenotypes. The predominant expression of the g ene in the developing brain, as well as its association with neuron di fferentiation, indicates that mutations of this gene might result in a mental retardation (MR) phenotype. In this paper we present a family with a splice junction mutation in XNP that results in the skipping of an exon and in the introduction of a stop codon in the middle of the XNP-coding sequence. Only the abnormal transcript is expressed in two first cousins presenting the classic ATR-X phenotype (with alpha-thala ssemia and HbH inclusions). In a distant cousin presenting a similar d ysmorphic MR phenotype but not having thalassemia, similar to 30% of t he XNP transcripts are normal. These data demonstrate that the mode of action of the XNP gene product on globin expression is distinct from its mode of action in brain development and facial morphogenesis and s uggest that other dysmorphic mental retardation phenotypes, such as Ju berg-Marsidi or some sporadic cases of Coffin-Lowry, could be due to m utations in XNP.