The human doublesex-related gene, DMRT2 is homologous to a gene involved in somitogenesis and encodes a potential bicistronic transcript

Intense efforts are currently being pursued to identify autosomal genes ass ociated with 46,XY male-to-female sex reversal. The genes DMRT1 and 2 are l ocated on distal 9p, a region deleted in 46,XY sex-reversed patients. They are considered excellent candidates because of their homology to regulators of sex development in invertebrates. We present the genomic structure of D MRT2, showing that it generates several transcripts with distinct coding po tential. In addition to the previously reported 226-amino-acid protein-enco ding transcript, we describe other mRNA isoforms that are potentially bicis tronic and are predicted to encode an. additional 328-amino-acid polypeptid e, Finally, a stop codon-containing exon (exon 4) can be skipped by alterna tive splicing and can generate a transcript that is predicted to encode a f usion protein. The latter shares 58% amino acid identity with a gene recent ly described in fish, termed terra. Differences in expression pattern exist for DMRT2 mRNA isoforms among the human adult tissues tested, between adul t tissues and human embryos, and between DMRT2 and DMRT1 during embryonic d evelopment. We failed to detect mutations by sequencing of DMRT2 in a sampl e of 46,XY female patients. The interesting structure of DMRT2 coupled to p reliminary functional studies in fish showing that terra is involved in som itogenesis suggests that validation or exclusion of this gene as a cause of sex reversal will require more in-depth investigations. (C) 2000 Academic Press.