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, shows frequent loss of material from human chromosome 22. Homozygous and heterozygous deletions in meningiomas defined a candidate region of >1 Mbp in 22q12.3-q13.1 and directed us to gene cloning in this segment. We characterized a new member of the N-acetylglucosaminyltransferase gene family, the LARGE gene. It occupies >664 kilobases and is one of the largest human genes. The predicted 756-aa N-acetylglucosaminyltransferase encoded by LARGE displays features that are absent in other glycosyltransferases. The human like-acetylglucosaminyltransferase polypeptide is much longer and contains putative coiled-coil domains. We characterized the mouse LARGE ortholog, which encodes a protein 97.75% identical with the human counterpart. Both genes reveal ubiquitous expression as assessed by Northern blot analysis and in situ 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 overexpress ganglioside GD3 (NeuAcalpha2,8NeuAcalpha2, 3Galbeta1,4Glc-Cer), which in meningiomas correlates with deletions on chromosome 22. It is the first time that a glycosyltransferase gene is involved in tumor-specific genomic rearrangements. An abnormal function of the human like-acetylglucosaminyltransferase 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.
Peyrard
M
M
Department of Molecular Medicine, Karolinska Hospital, S-171 76 Stockholm, Sweden.
Seroussi
E
E
Sandberg-Nordqvist
A C
AC
Xie
Y G
YG
Han
F Y
FY
Fransson
I
I
Collins
J
J
Dunham
I
I
Kost-Alimova
M
M
Imreh
S
S
Dumanski
J P
JP
D000595:Amino Acid Sequence; D000818:Animals; D002874:Chromosome Mapping; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D003001:Cloning, Molecular; D005732:Gangliosides / Q000235:genetics; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D016695:Glycosyltransferases / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008577:Meningeal Neoplasms / Q000235:genetics*; D008579:Meningioma / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D011487:Protein Conformation; D012333:RNA, Messenger / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
D005732:Gangliosides; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D016695:Glycosyltransferases; C117674:LARGE1 protein, human; D017351:N-Acetylglucosaminyltransferases