A transcription factor involved in skeletal muscle gene expression is deleted in patients with Williams syndrome

Williams-Beuren syndrome (WS) is a developmental disorder caused by a hemiz ygous microdeletion of approximately 1.4MB at chromosomal location 7q11.23. The transcription map of the WS critical region is not yet complete. We ha ve isolated and characterised a 3.4 kb gene, GTF3, which occupies about 140 kb of the deleted region. Northern blot analysis showed that the gene is e xpressed in skeletal muscle and heart, and RT-PCR analysis showed expressio n in a range of adult tissues with stronger expression in foetal tissues. P art of the conceptual GTF3 protein sequence is almost identical to a recent ly reported slow muscle-fibre enhancer binding protein MusTRD1, and shows s ignificant homology to the 90 amino-acid putative helix-loop-helix repeat ( HLH) domains of the transcription factor TFII-I (encoded for by the gene GT F2I). These genes may be members ok a new family of transcription factors c ontaining this HLH-like repeated motif, Both GTF3 and GTF2I map within the WS deleted region, with GTF2I being positioned distal to GTF3. GTF3 is dele ted in patients with classic WS, but not in patients we have studied with p artial deletions of the WS critical region who have only supravalvular aort ic stenosis, A feature of WS is abnormal muscle fatiguability, and we sugge st that haploinsufficiency of the GTF3 gene may be the cause of this.