Mutational analysis of the DAL-1/4.1B tumour-suppressor gene locus in meningiomas.
The DAL-1/41B gene (differentially expressed in adenocarcinoma of the lung), located in the chromosome 18p11.3 region, belongs to the protein family 4.1 (membrane-associated proteins), which includes the product of the NF2 gene (merlin), and the proteins, ezrin, radixin, and moesin. DAL-1/4.1B is normally expressed at high levels in the brain, with lower levels in the kidney, intestine, and testis. DAL-1/4.1B is known to suppress growth in meningiomas and can be lost in about 60% of sporadic meningiomas as an early event in tumorigenesis; it is a critical growth regulator in the pathogenesis of neoplastic transformation. The similarity between the DAL-1/4.1B protein and merlin, with their high levels of expression in the brain and their recurrent loss in meningiomas, and the lack of previous DAL-1/4.1B mutational analysis reports initiated this mutational study of DAL-1/4.1B in a series of 83 meningiomas. We found the following sequence variations; Ala555Thr (G1663A in exon 13) and Thr950Lys (C2849A in exon 19) in two cases each, and one case with a 5pb deletion (del taaaa) in intron 18. A polymorphism in exon 14 (C2112T/Thr704Thr, also known as C2166T) was also identified; the tumoral allelic constitutions were heterozygous C/T in 15, homo- or hemizygous C in 67 and hemizygous T in one tumour. The low mutational frequency in our study discounts sequence variations in DAL-1/4.1B as the main mechanism underlying participation of this gene in the neoplastic transformation of meningiomas, and suggests that other inactivating mechanisms, such as epigenetic changes, may participate in DAL1/4.1B silencing.
Martinez-Glez
Victor
V
Unidad de Investigación, Laboratorio de Oncogenetica Molecular, Hospital Universitario La Paz, Paseo Castellana 261, 28046 Madrid, Spain.
Bello
M Josefa
MJ
Franco-Hernandez
Carmen
C
De Campos
Jose M
JM
Isla
Alberto
A
Vaquero
Jesus
J
Rey
Juan A
JA
D000483:Alleles; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008577:Meningeal Neoplasms / Q000235:genetics*; D008579:Meningioma / Q000235:genetics*; D008840:Microfilament Proteins; D009154:Mutation; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D018807:Polymorphism, Single-Stranded Conformational; D017384:Sequence Deletion; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D004273:DNA, Neoplasm; C116887:EPB41L3 protein, human; D008565:Membrane Proteins; D008840:Microfilament Proteins; D025521:Tumor Suppressor Proteins