Document Detail

Functional evaluation of missense variations in the human MAD1L1 and MAD2L1 genes and their impact on susceptibility to lung cancer.
MedLine Citation:
PMID:  20516147     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Human MAD1 mitotic arrest deficient-like 1 (MAD1L1) and MAD2 mitotic arrest deficient-like 1 (MAD2L1) are two interactive proteins playing important roles in maintaining spindle checkpoint function. This study examined the functional relevance of missense coding single nucleotide polymorphisms (SNPs) in MAD1L1 and MAD2L1 and their association with susceptibility to lung cancer.
METHODS: SNPs in the MAD2L1 coding region were discovered by sequencing and impact of MAD1L1 and MAD2L1 variants on spindle checkpoint function was examined by flow cytometry and mitotic index assay. The associations of MAD1L1 and MAD2L1 variants with lung cancer were analysed in a case-control cohort of 1000 patients and 1000 controls. ORs and 95% CIs were estimated by logistic regression.
RESULTS: A novel C-to-A SNP at codon 84 of MAD2L1 (Leu84Met substitution) was discovered. Cells expressing MAD2L1-84Met and MAD1L1-558His had impaired spindle checkpoint function, with a lower 4N-DNA content and mitotic index when treated with nocodazole. Case-control analysis showed that the MAD2L1 Leu84Met SNP was associated with increased risk of lung cancer in an allele dose dependent manner, with the ORs being 2.55 (95% CI 1.95 to 3.33) for the Leu/Met and 2.68 (95% CI 2.05 to 3.48) for the Met/Met genotype compared with the Leu/Leu genotype. The MAD1L1 558 His/His genotype was also associated with 1.4-fold elevated lung cancer risk compared with the Arg/Arg genotype.
CONCLUSION: These results suggest that genetic variants in MAD1L1 and MAD2L1 confer susceptibility to lung cancer, which might result from reduced spindle checkpoint function due to attenuated function of MAD1L1 and/or MAD2L1.
Yongli Guo; Xuemei Zhang; Ming Yang; Xiaoping Miao; Yuankai Shi; Jiarui Yao; Wen Tan; Tong Sun; Dan Zhao; Dianke Yu; Junniao Liu; Dongxin Lin
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-06-01
Journal Detail:
Title:  Journal of medical genetics     Volume:  47     ISSN:  1468-6244     ISO Abbreviation:  J. Med. Genet.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-08-27     Completed Date:  2010-12-15     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985087R     Medline TA:  J Med Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  616-22     Citation Subset:  IM    
State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, China.
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MeSH Terms
Amino Acid Sequence
Base Sequence
Calcium-Binding Proteins / chemistry,  genetics*,  metabolism
Case-Control Studies
Cell Cycle Proteins / chemistry,  genetics*,  metabolism
Cell Line, Tumor
DNA, Neoplasm / metabolism
Gene Frequency / genetics
Genetic Predisposition to Disease*
Lung Neoplasms / genetics*
Middle Aged
Mitotic Index
Mitotic Spindle Apparatus / metabolism
Molecular Sequence Data
Mutation, Missense / genetics*
Nuclear Proteins / genetics*,  metabolism
Open Reading Frames / genetics
Polymorphism, Single Nucleotide / genetics
Protein Binding
Repressor Proteins / chemistry,  genetics*,  metabolism
Reg. No./Substance:
0/Calcium-Binding Proteins; 0/Cell Cycle Proteins; 0/DNA, Neoplasm; 0/MAD1L1 protein, human; 0/MAD2L1 protein, human; 0/Nuclear Proteins; 0/Repressor Proteins

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