Pemov Alexander, Sung Heejong, Hyland Paula L, Sloan Jennifer L, Ruppert Sarah L, Baldwin Andrea M, Boland Joseph F, Bass Sara E, Lee Hyo Jung, Jones Kristine M, Zhang Xijun, Mullikin James C, Widemann Brigitte C, Wilson Alexander F, Stewart Douglas R
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America.
Genometrics Section, Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, United States of America.
PLoS Genet. 2014 Oct 16;10(10):e1004575. doi: 10.1371/journal.pgen.1004575. eCollection 2014 Oct.
Neurofibromatosis type 1 (NF1) is an autosomal dominant, monogenic disorder of dysregulated neurocutaneous tissue growth. Pleiotropy, variable expressivity and few NF1 genotype-phenotype correlates limit clinical prognostication in NF1. Phenotype complexity in NF1 is hypothesized to derive in part from genetic modifiers unlinked to the NF1 locus. In this study, we hypothesized that normal variation in germline gene expression confers risk for certain phenotypes in NF1. In a set of 79 individuals with NF1, we examined the association between gene expression in lymphoblastoid cell lines with NF1-associated phenotypes and sequenced select genes with significant phenotype/expression correlations. In a discovery cohort of 89 self-reported European-Americans with NF1 we examined the association between germline sequence variants of these genes with café-au-lait macule (CALM) count, a tractable, tumor-like phenotype in NF1. Two correlated, common SNPs (rs4660761 and rs7161) between DPH2 and ATP6V0B were significantly associated with the CALM count. Analysis with tiled regression also identified SNP rs4660761 as significantly associated with CALM count. SNP rs1800934 and 12 rare variants in the mismatch repair gene MSH6 were also associated with CALM count. Both SNPs rs7161 and rs4660761 (DPH2 and ATP6V0B) were highly significant in a mega-analysis in a combined cohort of 180 self-reported European-Americans; SNP rs1800934 (MSH6) was near-significant in a meta-analysis assuming dominant effect of the minor allele. SNP rs4660761 is predicted to regulate ATP6V0B, a gene associated with melanosome biology. Individuals with homozygous mutations in MSH6 can develop an NF1-like phenotype, including multiple CALMs. Through a multi-platform approach, we identified variants that influence NF1 CALM count.
1型神经纤维瘤病（NF1）是一种常染色体显性单基因疾病，其神经皮肤组织生长失调。多效性、可变表达以及少数NF1基因型与表型的相关性限制了NF1的临床预后。NF1的表型复杂性被认为部分源于与NF1基因座不连锁的遗传修饰因子。在本研究中，我们假设种系基因表达的正常变异会导致NF1中某些表型的风险。在一组79名NF1患者中，我们研究了淋巴母细胞系中的基因表达与NF1相关表型之间的关联，并对具有显著表型/表达相关性的选定基因进行了测序。在一个由89名自我报告为欧洲裔美国人的NF1患者组成的发现队列中，我们研究了这些基因的种系序列变异与咖啡牛奶斑（CALM）计数之间的关联，CALM计数是NF1中一种易于处理的肿瘤样表型。DPH2和ATP6V0B之间的两个相关常见单核苷酸多态性（SNP，rs4660761和rs7161）与CALM计数显著相关。平铺回归分析也确定SNP rs4660761与CALM计数显著相关。错配修复基因MSH6中的SNP rs1800934和12个罕见变异也与CALM计数相关。在一个由180名自我报告为欧洲裔美国人组成的联合队列的荟萃分析中，SNP rs7161和rs4660761（DPH2和ATP6V0B）均具有高度显著性；在假设次要等位基因具有显性效应的荟萃分析中，SNP rs1800934（MSH6）接近显著性。预测SNP rs4660761可调节ATP6V0B，该基因与黑素小体生物学相关。MSH6纯合突变的个体可出现类似NF1的表型，包括多个CALM。通过多平台方法，我们鉴定出了影响NF1患者CALM计数的变异。
