Deletion of 11 amino acids in tuberin associated with severe tuberous sclerosis phenotypes: evidence for a new essential domain in the first third of the protein.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder displaying a large spectrum of symptoms. Linkage studies have shown two loci, TSC1 in 9q34 and TSC2 in 16p13.3, to be involved in the disease. The TSC2 gene, composed of 41 exons, has been isolated and is shown to encode a protein, tuberin, from a 5.5-kb transcript. Mutation screening for both clinical diagnosis and identification of functional domains within the tuberin is in progress. In this study we identify a 33-bp in-frame deletion (1462del33) in the mRNA which segregates in two unrelated French families with severe TSC phenotypes. The corresponding 11 amino acids deletion (aa 482-492) is shown to result from two different splice site mutations at exon 14 and, when compared with the position of two previously described missense mutations, indicates a novel functionally important region of the protein.