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The Human LARGE Gene from 22Q12.3-Q13.1 Is a New, Distinct Member of the Glycosyltransferase Gene Family

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The Human LARGE Gene from 22Q12.3-Q13.1 Is a New, Distinct Member of the Glycosyltransferase Gene Family Proc. Natl. Acad. Sci. USA Vol. 96, pp. 598–603, January 1999 Genetics The human LARGE gene from 22q12.3-q13.1 is a new, distinct member of the glycosyltransferase gene family MYRIAM PEYRARD*, EYAL SEROUSSI*, ANN-CHRISTIN SANDBERG-NORDQVIST*, YA-GANG XIE*, FEI-YU HAN*, INGEGERD FRANSSON*, JOHN COLLINS†,IAN DUNHAM†,MARIA KOST-ALIMOVA‡§,STEPHAN IMREH‡, AND JAN P. DUMANSKI*¶ *Department of Molecular Medicine, Karolinska Hospital, S-171 76 Stockholm, Sweden; †Sanger Centre, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, United Kingdom; ‡Microbiology and Tumor Biology Center, Karolinska Institutet, S-171 77 Stockholm, Sweden; and §Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 117984 Moscow, Russia Communicated by Rolf Luft, Karolinska Hospital, Stockholm, Sweden, November 20, 1998 (received for review September 15, 1998) ABSTRACT Meningioma, a tumor of the meninges cov- glycosphingolipid sugar chains within different compartments ering the central nervous system, shows frequent loss of of the Golgi network (5). Analysis of sequences from mam- material from human chromosome 22. Homozygous and malian GTs cloned so far indicates a family with low sequence heterozygous deletions in meningiomas defined a candidate conservation but with similar protein structure. They all are region of >1 Mbp in 22q12.3-q13.1 and directed us to gene between 330–560 amino acids long and share the same type II y transmembrane protein structure (Nin Cout) with four main cloning in this segment. We characterized a new member of the y N-acetylglucosaminyltransferase gene family, the LARGE domains: a short cytoplasmic domain, a targeting membrane- gene. It occupies >664 kilobases and is one of the largest anchoring domain, a stem region, and a catalytic domain. The human genes. The predicted 756-aa N-acetylglucosaminyl- latter two are located within the Golgi cisternae (5). Glycosphingolipids are composed of sphingosine, fatty acid transferase encoded by LARGE displays features that are chain, and oligosaccharide head, which constitutes the basis for absent in other glycosyltransferases. The human like- their diversity. Gangliosides are complex glycosphingolipids acetylglucosaminyltransferase polypeptide is much longer containing sialic acid residues in their oligosaccharide head. and contains putative coiled-coil domains. We characterized Gangliosides participate in various cellular processes, and the mouse LARGE ortholog, which encodes a protein 97.75% there is evidence for their role in tumorigenesis: e.g., the identical with the human counterpart. Both genes reveal composition of gangliosides has been shown to change on ubiquitous expression as assessed by Northern blot analysis cellular transformation (6, 7). This process is believed to and in situ histochemistry. Chromosomal mapping of the increase tumorigenicity andyor to affect the metastatic capac- mouse gene reveals that mouse chromosome 8C1 corresponds ity of tumor cells. Some growth factor receptors appears to be to human 22q12.3-q13.1. Abnormal glycosylation of proteins regulated by gangliosides, among them ganglioside GD3. and glycosphingolipids has been shown as a mechanism Gangliosides may inhibit dimerization of growth factor recep- behind an increased potential of tumor formation andyor tors and thus may modify their actions (8). Melanoma was progression. Human tumors overexpress ganglioside GD3 shown to overexpress gangliosides GD3 and GD2, and clinical (NeuAca2,8NeuAca2,3Galb1,4Glc-Cer), which in meningio- trials using antibodies mimicking GD3 or GD2 resulted in mas correlates with deletions on chromosome 22. It is the first inhibition of tumor growth in a number of patients (9, 10). time that a glycosyltransferase gene is involved in tumor- Meningioma also has been studied for its content of ganglio- specific genomic rearrangements. An abnormal function of sides and has been divided into ganglioside GM3 (NeuAca2,3Galb1,4Glc-Cer)- and GD3-rich groups (11). It the human like-acetylglucosaminyltransferase protein may be also has been shown that monosomy 22 in meningiomas linked to the developmentyprogression of meningioma by y correlates with a high GD3 content (12). Moreover, there is a altering the composition of gangliosides and or by effect(s) on connection between monosomy 22 and an increased aggres- other glycosylated molecules in tumor cells. siveness of meningioma because deletions on chromosome 22 correlate with signs of tumor recurrence (13). Human chromosome 22 is the second smallest autosome and We report here the cloning of a novel, distinct member of the is rich in genes of medical interest. A considerable number of N-acetylglucosaminyltransferase gene family, the LARGE tumors exhibit deletions on this chromosome, suggesting that gene, from a region on human chromosome 22 that previously it contains several cancer-related genes that have not yet been was shown to be affected by interstitial tumor deletions. An abnormal function of the human like-acetylglucosaminyltrans- characterized (1). Meningioma is one of the tumors that y frequently display total or partial deletions on chromosome 22 ferase (LARGE) protein may be linked to the development progression of meningioma by altering the composition of (2–4). Previous studies revealed several regions on 22q that y were targeted by interstitial homozygous andyor heterozygous gangliosides and or by effect(s) on other glycosylated mole- cules in tumor cells. tumor-specific deletions, and these regions may therefore harbor tumor suppressor genes. One of the regions was defined by a combination of two interstitial deletions—a homozygous MATERIALS AND METHODS deletion in one tumor and a heterozygous deletion in another . Physical Mapping, Analysis of Genomic Sequence, and (4)—and delineated a segment of 1 Mbp in 22q12.3-q13.1. cDNA Screening. The contig was constructed and exon am- These findings prompted us to investigate the gene content of this chromosomal region. Abbreviations: LARGE, human like-acetylglucosaminyltransferase; Glycosyltransferases (GTs) constitute a heterogeneous FISH, fluorescent in situ hybridization; acc., European Molecular group of enzymes that carry out synthesis of glycoprotein and Biology LaboratoryyGenBank accession number; GT, glycosyltrans- ferase; kb, kilobase; PAC, P1-derived artificial chromosome. The publication costs of this article were defrayed in part by page charge Data deposition: The sequences reported in this paper have been deposited in the GenBank database [accession nos. AJ007583 payment. This article must therefore be hereby marked ‘‘advertisement’’ in (LARGE cDNA sequence) and AJ006278 (Large cDNA sequence)]. accordance with 18 U.S.C. §1734 solely to indicate this fact. ¶To whom reprint request should be addressed. e-mail: Jan.Dumanski@ PNAS is available online at www.pnas.org. cmm.ki.se. 598 Downloaded by guest on October 3, 2021 Genetics: Peyrard et al. Proc. Natl. Acad. Sci. USA 96 (1999) 599 plification was applied to 24 cosmids from the region as a fluorescence microscope (LEITZ-DMRB, Leica, Heidel- described (14–16). Analysis of sequences was performed by berg). using the XGRAIL2 program (17). Predicted exons were tested by PCR in the following cDNA libraries: fetal brain, fetal RESULTS muscle, adult muscle, fetal spleen, pancreatic adenocarcinoma, and testis (Stratagene, catalog nos. 936206, 836201, 937209, Mapping of the Region Deleted in Tumors 11 and 119A and 937205, 937208, and 939202, respectively) and fetal brain and Construction of a Genomic Contig. Previous deletion mapping thyroid (CLONTECH, catalog nos. HL3003a and HL3019a, of 170 sporadic meningiomas revealed two cases (11 and 119) respectively). DNA fragments were labeled radioactively by with interstitial deletions centered around marker KI-844 (4). PCR (18) or by random priming (19). cDNA screening of We refined here the breakpoint location of the deletions by human fetal brain (Stratagene, catalog no. 936206), mouse using the following eight markers: KI-1186, KI-844, KI-106, early embryo, and mouse brain (CLONTECH, catalog no. KI-117, KI-711, W23C, KI-261, and the MB (myoglobin) gene ML3000a) libraries was performed as described (20). (Fig. 1). Loss of heterozygosity in tumor 11, defining the extent Sequencing and Bioinformatics. cDNA sequencing was of heterozygous deletion, was observed for the above markers, performed by using BigDye-Terminators (Applied Biosys- except KI-1186 at the centromeric side and W23C, KI-261, and tems) (21). Sequencing products were separated by using MB at the telomeric side of the deletion. The tumor 119 LongRanger (FMC) on ABI377 (Applied Biosystems). Se- originally was divided into multiple sections, and three of them quences were assembled by using the GAP4 program (22). were analyzed molecularly. On refined analysis, section 119A cDNAs were sequenced with a minimal redundancy of 8.7 displayed a homozygous deletion for all above-mentioned reading character per consensus character and at least one markers except for KI-1186 and MB. The overlap between sequencing read on each strand. Repeats were filtered out by yy these deletions can be estimated to 1.5 Mbp between markers using REPEAT MASKER (http: www.ftp.genome.washing- KI-844 and KI-711 (30). Using the probes previously mapped ton.edu). The BLAST programs were used on the National y to this part of chromosome 22 (31, 32), we constructed and Center for Biotechnology Information National Institutes of present here a physical map over the deleted area, based on a Health
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