Heterozygous carriers of Nijmegen Breakage Syndrome have a distinct gene expression phenotype

Abstract

Autosomal recessive diseases are those that require mutations in both alleles to exhibit the disorder. Although most recessive conditions are rare, heterozygous carriers of recessive mutations are quite common. In this study, we show that carriers of Nijmegen Breakage Syndrome (NBS) have a distinct gene expression phenotype that differs from that of noncarriers and also from that of carriers of a similar syndrome, Ataxia Telangiectasia (AT). We found 520 genes whose expression levels differ significantly (P Յ 0.001) between NBS carriers and controls. By linear discriminant analysis, we found a combination of 16 genes that allows 100% correct classification of individuals as either NBS carriers or noncarriers in a training set with 25 individuals, and in a test set with 52 individuals. When applied to AT carriers, the discriminant function misclassified only one out of 18 AT carriers as an NBS carrier. Our result shows that NBS carriers have a specific gene expression phenotype. It suggests that heterozygous mutations can contribute significantly to natural variation in gene expression. This has implications for the role that heterozygosity for recessive diseases plays in the overall genetic architecture of complex human traits and diseases.[Supplemental material is available online at www.genome.org. The microarray data from this study have been submitted to NCBI/GEO under accession no. GSE3894.]Nijmegen Breakage Syndrome (NBS; MIM 251260) is an autosomal recessive disease caused by mutations in the NBS gene (nibrin) on chromosome 8q21 (Saar et al. 1997;Carney et al. 1998;Varon et al. 1998). It is characterized by microcephaly, growth retardation, immunodeficiency, and predisposition to cancer. NBS belongs to a group of chromosomal instability disorders that also includes Ataxia Telangiectasia (AT), Bloom's syndrome, and Fanconi's anemia. The cellular hallmarks of these disorders are chromosomal rearrangements, sensitivity to ionizing radiation, and defects in cell cycle checkpoint. Nibrin is a component of the hMre/hRad50 complex that plays a key role in cellular DNA damage response (Carney et al. 1998). NBS is a rare disease. However, the frequency of heterozygous carriers is estimated to be as high as 1/150 in the Slavic population (Varon et al. 2000;Drabek et al. 2002). A founder mutation, 657del5, was identified in many patients of Slavic descent; nevertheless, there are patients with other mutations in the nibrin gene (Varon et al. 1998). Studies have shown that although NBS is an autosomal recessive disorder, heterozygous carriers have an increased risk of cancer and sensitivity to radiation (Dumon-Jones et al. 2003;Resnick et al. 2003;Cybulski et al. 2004). While polymerase chain reaction with sequence-specific primers can reliably detect carriers of the common 657del5 mutations (Drabek et al. 2002), it is not practical for identifying carriers of other nibrin mutations. Studies have attempted to classify carriers of NBS by radiosensitivity assays, but it was found that the assays lack sensitivity (Tanza...

A genetic model of differential susceptibility to human respiratory syncytial virus (RSV) infection

“…We next sought insight into mechanisms of differential responsiveness to RSV in LCLs by infecting 42 HapMap CEU LCLs to leverage genetic and genomic information available for the lines (31–35). As above, we found significant interindividual variation in viral RSV‐G expression following infection with RSV ( Fig.…”

“…37; and GSE11582, ref. 31) from the U.S. National Center for Biotechnology Information (NCBI; Bethesda, MD, USA) Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/) for the LCLs. We then used a 3‐step approach: first, we performed linear regression of log 2 ‐transformed RSV‐G expression on log 2 ‐transformed gene expression values of every detectable gene; second, we compared the average gene expression levels for the 5 individuals with the highest RSV‐G expression against that for the 5 individuals with the lowest RSV‐G expression using t test (Fig.…”

The Slavic NBN Founder Mutation: A Role for Reproductive Fitness?

“…This anomalous chromosomal behaviour still persists during the first mitotic divisions[65] and is paralleled by diminished mRNA levels of several checkpoint proteins and also of cohesin (reviewed in [66]). Carriers of the NBN c.657del5 mutation have a distinct gene expression phenotype with about the same number of genes up- and down regulated [67]. Moreover, based upon SDS-PAGE and mass spectrometry, it was shown that the two truncated proteins, p26 and p70, synthesized by carriers of the mutation, bind to proteins that do not interact with full-length nibrin [68].…”

Increased risk of larynx cancer in heterozygous carriers of the I171V mutation of the NBS1 gene

“…(17) Heterozygous mutations in the NBS1 gene have been described in various groups of cancer patients, for example, patients with acute lymphoblastic leukemia (ALL), (18,19) non-Hodgkin's lymphoma (NHL), (20) and in cancer cell lines.…”

“…(14) Recent findings show that besides spontaneous chromosome instability, (15,16) cells from NBS1 gene mutation carriers are characterized by a distinct gene expression phenotype. (17) Heterozygous mutations in the NBS1 gene have been described in various groups of cancer patients, for example, patients with acute lymphoblastic leukemia (ALL), (18,19) non-Hodgkin's lymphoma (NHL), (20) and in cancer cell lines. (21) Recent studies strongly suggest that heterozygous 657del5 mutation carriers have an elevated risk of malignant tumor development, especially of melanoma, (22,23) colon and rectum cancer, (23) prostate cancer, (24) ovarian cancer, (25) breast cancer (26,27) and NHL.…”