The human LARGE gene from 22q12,3-q13.1 is a new, distinct member of the glycosyltransferase gene family

Meningioma, a tumor of the meninges covering the central nervous system, sh ows frequent loss of material from human chromosome 22, Homozygous and hete rozygous deletions in meningiomas defined a candidate region of >1 Mbp in 2 2q12.3-q13.1 and directed us to gene cloning in this segment. We characteri zed a new member of the N-acetylglucosaminyltransferase gene family, the LA RGE gene. It occupies >664 kilobases and is one of the largest human genes. The predicted 756-aa N-acetylglucosaminyltransferase encoded by LARGE disp lays features that are absent in other glycosyltransferases. The human like -acetylglucosaminyltransferase polypeptide is much longer and contains puta tive coiled-coil domains. We characterized the mouse LARGE ortholog, which encodes a protein 97.75% identical with the human counterpart. Both genes r eveal ubiquitous expression as assessed by Northern blot analysis and in si tu histochemistry, Chromosomal mapping of the mouse gene reveals that mouse chromosome 8C1 corresponds to human 22q12.3-q13.1. Abnormal glycosylation of proteins and glycosphingolipids has been shown as a mechanism behind an increased potential of tumor formation and/or progression. Human tumors ove rexpress ganglioside GD3 (NellAc alpha 2,8NeuAc alpha 2,3Gal beta 1,4Glc-Ce r), which in meningiomas correlates with deletions on chromosome 22, It is the first time that a glycosyltransferase gene is involved in tumor-specifi c genomic rearrangements. An abnormal function of the human like-acetylgluc osaminyltransferase protein may be linked to the development/progression of meningioma by altering the composition of gangliosides and/or by effect(s) on other glycosylated molecules in tumor cells.