New gene family defined by MORC, a nuclear protein required for mouse spermatogenesis

Mammalian spermatogenesis is a complex developmental process, The analysis of mouse mutations has provided insight into biochemical pathways required for completion of this process. We previously described the autosomal reces sive mouse morc(TgN(Tyr)1Az) (microrchidia) mutation, a serendipitous trans genic insertional mutation which causes arrest of spermatogenesis prior to the pachytene stage of meiosis prophase I. We now report the molecular char acterization of the more locus and positional cloning of a gene disrupted b y the morc(TgN(Tyr)1Az) mutation. This gene, which we term Morc, encodes a 108 kDa protein expressed specifically in male germ cells, The transgene in tegrated within the first intron of Morc and was accompanied by an intragen ic deletion of similar to 13 kb of genomic sequences, removing exons 2-4 an d abrogating expression of the wild-type transcript. Analysis of the MORC p rotein sequence revealed putative nuclear localization signals, two predict ed coiled-coil structural motifs and limited homology to GHL (GyraseB, Hsp9 0, MutL) ATPase, Epitope-tagged MORC protein expressed in COS7 cells locali zed to the nucleus. We also cloned the human MORC homolog and show that it too is testis-specific, but closely related human genes are transcribed in multiple somatic tissues. Homologous proteins are also present in zebrafish , nematodes, slime mold and plants. Thus, cloning of More defines a novel g ene family whose members are likely to serve important biological functions in both meiotic and mitotic cells of multicellular organisms.