Genetic alterations of protein-o-mannosyltransferase-1 in glioneuronal and glial brain tumors with subarachnoid spread.
Leptomeningeal spread is a casual but conspicuous finding in both low- and high-grade gliomas. We hypothesized a compromised integrity of the glia limitans-basal lamina complex due to glycosylation defects by loss of protein-o-mannosyltransferase-1 (POMT1) activity, also a well-known feature in developmental brain disorders with leptomeningeal heterotopia. Hypothesizing it as analogous in gliomas, we have performed a comprehensive polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis of the POMT1 gene in 41 brain tumor specimens. Each specimen was subjected to laser capture microdissection analyses to dissect: (i) subarachnoid tumor components; (ii) deeply localized tumor areas; and (iii) histologically unaffected CNS fragments. In addition, leukocyte DNA of healthy Caucasians served as controls (n = 100). Sequence alterations were found in exons 7, 9, 15 and 18. Exon 7 bore two sequence alterations, one 751C > T transition with amino acid exchange of arginine by tryptophane (Arg251Trp) (n = 12/41 in Tu vs n = 7/82 in Co) and a 752G > A transition with replacement of arginine by glutamine (Arg251Gln) (n = 3/41 in Tu vs n = 0/82 in Co) that were significantly increased in the tumor specimens compared to controls (P < 0.05). A 979G > A transition in exon 9 resulted in a valine to isoleucine switch (Val327Ile) (n = 6/40 in Tu vs n = 4/84 in Co). Individual specimens revealed a 1565G > A (Arg522Lys) transition in exon 15 and a 1922C > T (Ala641Val) transition in exon 18. Two gangliogliomas only revealed sequence alterations in the superficial area but not in intraparenchymal and adjacent control specimens. We conclude that a significant increase of POMT1 missense mutations may indicate a functional role in neoplastic conditions in individual tumors. Future studies will be important to evaluate a functional impact of POMT1 alterations in human brain tumors.
Snoei
Julia
J
Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany. jsnoei@uni-bonn.de
Urbach
Horst
H
Engels
Gudrun
G
Fassunke
Jana
J
von Lehe
Marec
M
Becker
Albert J
AJ
Majores
Michael
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005910:Glioma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008364:Mannosyltransferases / Q000235:genetics*; D042282:Microdissection; D008875:Middle Aged; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D013346:Subarachnoid Space; D055815:Young Adult
D008364:Mannosyltransferases; C082696:protein O-mannosyltransferase