DELETION OF THE H19 TRANSCRIPTION UNIT REVEALS THE EXISTENCE OF A PUTATIVE IMPRINTING CONTROL ELEMENT

The distal region of mouse chromosome 7 contains a cluster of imprinte d genes that includes H19 and Igf2 (insulin-like growth factor 2). H19 is expressed as an untranslated RNA found at high levels in endoderma l and mesodermal embryonic tissues. This gene is imprinted and exclusi vely expressed from the allele of maternal origin. The Igf2 gene shows a similar pattern of expression but is expressed from the paternal al lele. We have generated a targeted deletion of the H19 transcription u nit by insertion of a neo replacement cassette. The homozygous mutant animals are viable and fertile and display an overgrowth phenotype of 8% compared with wild-type littermates. This is associated with the di sruption of Igf2 imprinting and the consequent biallelic expression of this gene. A striking feature of the recombinant H19 allele is the oc currence of a parental imprint set on the neo replacement cassette. Th erefore imprinting of the H19 locus is independent of the H19 gene its elf. Taken together with the results of a larger H19 mutation describe d previously, this indicates that an imprinting control element is loc ated within the region 10 kb upstream of H19.