ATM gene mutations result in both recessive and dominant expression phenotypes of genes and microRNAs.
The defining characteristic of recessive disorders is the absence of disease in heterozygous carriers of the mutant alleles. However, it has been recognized that recessive carriers may differ from noncarriers in some phenotypes. Here, we studied ataxia telangiectasia (AT), a classical recessive disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. We compared the gene and microRNA expression phenotypes of noncarriers, AT carriers who have one copy of the ATM mutations, and AT patients with two copies of ATM mutations. We found that some phenotypes are more similar between noncarriers and AT carriers compared to AT patients, as expected for a recessive disorder. However, for some expression phenotypes, AT carriers are more similar to the patients than to the noncarriers. Analysis of one of these expression phenotypes, TNFSF4 level, allowed us to uncover a regulatory pathway where ATM regulates TNFSF4 expression through MIRN125B (also known as miR-125b or miR125b) [corrected] In AT carriers and AT patients, this pathway is disrupted. As a result, the level of MIRN125B is lower and the level of its target gene, TNFSF4, is higher than in noncarriers. A decreased level of MIRN125B is associated with breast cancer, and an elevated level of TNFSF4 is associated with atherosclerosis. Thus, our findings provide a mechanistic suggestion for the increased risk of breast cancer and heart disease in AT carriers. By integrating molecular and computational analyses of gene and microRNA expression, we show the complex consequences of a human gene mutation.
Smirnov
Denis A
DA
Departments of Pediatrics and Genetics, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cheung
Vivian G
VG
D064007:Ataxia Telangiectasia Mutated Proteins; D000071616:CDX2 Transcription Factor; D018797:Cell Cycle Proteins / Q000235:genetics*; D019295:Computational Biology / Q000379:methods; D004268:DNA-Binding Proteins / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D005808:Genes, Recessive; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D053278:OX40 Ligand / Q000235:genetics*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012306:Risk; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D053278:OX40 Ligand; C089251:TNFSF4 protein, human; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases