A NOVEL HOMEODOMAIN-ENCODING GENE IS ASSOCIATED WITH A LARGE CPG ISLAND INTERRUPTED BY THE MYOTONIC-DYSTROPHY UNSTABLE (CTG)(N) REPEAT

Myotonic dystrophy (DM) is associated with a (CTG)(n) trinucleotide re peat expansion in the 3'-untranslated region of a protein kinase-encod ing gene, DMPK, which maps to chromosome 19q13.3. Characterisation of the expression of this gene in patient tissues has thus far generated conflicting data on alterations in the steady state levels of DMPK mRN A, and on the final DMPK protein levels in the presence of the expansi on. The DM region of chromosome 19 is gene rich, and it is possible th at the repeat expansion may lead to dysfunction of a number of transcr iption units in the vicinity, perhaps as a consequence of chromatin di sruption. We have searched for genes associated with a CpG island at t he 3' end of DMPK, Sequencing of this region shows that the island ext ends over 3.5 kb and is interrupted by the (CTG)(n) repeat. Comparison of genomic sequences downstream (centromeric) of the repeat in human and mouse identified regions of significant homology. These correspond to exons of a gene predicted to encode a homeodomain protein. RT-PCR analysis shows that this gene, which we have called DM locus-associate d homeodomain protein (DMAHP), is expressed in a number of human tissu es, including skeletal muscle, heart and brain.