Identification of human candidate genes for male infertility by digital differential display

Evidence for the importance of genetic factors in male fertility is accumul ating. In the literature and the Mendelian Cytogenetics Network database, 2 65 cases of infertile males with balanced reciprocal translocations have be en described. The candidacy for infertility of 14 testis-expressed transcri pts (TETs) were examined by comparing their chromosomal mapping position to the position of balanced reciprocal translocation breakpoints found in the 265 infertile males, The 14 TETs were selected by using digital differenti al display (electronic subtraction) to search for apparently testis-specifi c transcripts in the TIGR database. The testis specificity of the 14 TETs w as further examined by reverse transcription-polymerase chain reaction (RT- PCR) on adult and fetal tissues showing that four TETs (TET1 to TET4) were testis-expressed only, six TETs (TET5 to TET10) appeared to be differential ly expressed and the remaining four TETs (TET11 to TET14) were ubiquitously expressed. Interestingly, the two tesis expressed-only transcripts, TET1 a nd TET2,mapped to chromosomal regions where seven and six translocation bre akpoints have been reported in infertile males respectively. Furthermore, o ne ubiquitously, but predominantly testis-expressed, transcript, TET11, map ped to 1p32-33, where 13 translocation breakpoints have been found in infer tile males, Interestingly, the mouse mutation, skeletal fusions with steril ity, sks, maps to the syntenic region in the mouse genome. Another transcri pt, TET7, was the human homologue of rat Tpx-1, which functions in the spec ific interaction of spermatogenic cells with Sertoli cells. TPX-1 maps to 6 p21 where three cases of chromosomal breakpoints in infertile males have be en reported. Finally, TET8 was a novel transcript which in the fetal stage is testis-specific, but in the adult is expressed in multiple tissues, incl uding testis, We named this novel transcript fetal and adult testis-express ed transcript (FATE).