Hereditary multiple exostoses (EXT) is an autosomal dominant disorder of enchondral bone formation characterized by multiple bony outgrowths (exostoses), with progression to osteosarcoma in a minority of cases. The exclusive involvement of skeletal abnormalities distinguishes EXT from the clinically more complex Langer-Giedion syndrome (LGS), which is associated with deletions at chromosome 8q24. Previously, linkage analysis has revealed a locus for EXT in the LGS region on chromosome 8q24. However, locus heterogeneity was apparent with 30% of the families being unlinked to 8q24. We report on two large pedigrees segregating EXT in which linkage to the LGS region was excluded. To localize the EXT gene(s) in these families we performed a genome search including 254 microsatellite markers dispersed over all autosomes and the X chromosome. In both families evidence was obtained for linkage to markers from the proximal short and long arms of chromosome 11. Two-point analysis gave the highest lod score for D11S554 (Zmax = 7.148 at theta = 0.03). Multipoint analysis indicated a map position for the EXT gene between D11S905 and D11S916, with a peak multipoint lod score of 8.10 at 6 cM from D11S935. The assignment of a second locus for EXT to the pericentromeric region of chromosome 11 implicates an area that is particularly rich in genes responsible for developmental abnormalities and neoplasia.

A human homologue of the rodent T cell mono ADPribosyl transferase RT6 mRNA was identified by a systematic analysis of human testis transcripts. This messenger encodes for a precursor protein of 367 aa (MW: 41.5 kDa) which exhibits a peptide signal, consensus domains for mono ADP-ribosyl transferase and a C-terminal part characteristic of glycophosphatidyl inositol anchored protein. This mRNA, transcribed from a gene localized in 4q13-q21, is not expressed in white blood cells but is specific for human testis in which it is likely to correspond to a new ADP-ribosyl transferase.

We cloned a human protein (Hzyg) homologue to Caenorhabditis elegans Zyg-11, an essential protein for cell division at the initial developmental stages of this species, and to a Drosophila melanogaster gene product (Mei-1) which is likely to be involved in meiosis. Hzyg mRNA encodes a protein of 766 amino acids (88 kDa), 14% of which are leucine residues, with some being arranged in four leucine rich repeat motives usually involved in protein-protein interactions. Hzyg is encoded by a single gene, located on chromosome 9q32-q34.1, and transcribed as two mRNA: a 5 kb transcript strongly expressed in testis and skeletal muscle and barely detectable in other human tissues, and an abundant 3.1 kb mRNA detected only in the testis. By using in-situ hybridization and immunohistochemistry, we clearly established the presence of Hzyg expression in pachytene spermatocytes (stage V) and spermatids (stage I and/or II) around the time of meiosis. The cell specific expression of Hzyg transcripts in testis, and the conservation of this gene among distant species, suggest that this protein may have an important role during meiosis.