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Genetic modifiers of neurofibromatosis type 1-associated café-au-lait macule count identified using multi-platform analysis.

Pemov A, Sung H, Hyland PL, Sloan JL, Ruppert SL, Baldwin AM, Boland JF, Bass SE, Lee HJ, Jones KM, Zhang X, NISC Comparative Sequencing ProgramMullikin JC, Widemann BC, Wilson AF, Stewart DR - PLoS Genet. (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Genome Browser (http://genome.ucsc.edu/) image of ATPV0B and DPH2 gene regions on human assembly hg19 based on NIH Epigenomics Roadmap data and ENCODE data [74], [76].The promoter CpG islands (CGIs) of ATPV0B (CGI: 121) is highlighted by a green filled box. Regulatory domains (chromatin state segmentation using a hidden Markov Model [ChromHMM)] and core histone marks: Crimson, flanking TSS; Red, active transcriptional start site (TSS); Dark Green: transcription elongation/transition; Yellow green: transcription enhancer-like; Orange, active-to-weak enhancer. MeDIP: methylated DNA immunoprecipitation, MRE: methylation-sensitive restriction enzyme sequencing, Melanocytes: normal primary penile foreskin melanocytes (UCSF-UBC-USC and UCSF-UBC), Fibroblasts: normal primary penile foreskin fibroblasts (UCSF-UBC-USC and UCSF-UBC), Keratinocytes: normal primary penile foreskin keratinocytes (UCSF-UBC-USC and UCSF-UBC), PBMCs: peripheral blood mononuclear cells (UCSF-UBC-UCD and UCSF UBC), and Lymphocytes:CD19, CD4 and CD8 cells (NIH Epigenomics Roadmap data). TF: transcription factors ChIP-seq (161 factors) from ENCODE with Factorbook Motifs. DNase I: Open chromatin DNase I hypersensitivity clusters in 125 cell types from ENCODE. SNPs rs4660761 and rs7161 are highlighted by colored boxes. Sources and acknowledgements for the UCSC genome, ENCODE, The NIH ROADMAP databases and extracted tracks http://genome.ucsc.edu/goldenPath/credits.html#human_credits.
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pgen-1004575-g001: Genome Browser (http://genome.ucsc.edu/) image of ATPV0B and DPH2 gene regions on human assembly hg19 based on NIH Epigenomics Roadmap data and ENCODE data [74], [76].The promoter CpG islands (CGIs) of ATPV0B (CGI: 121) is highlighted by a green filled box. Regulatory domains (chromatin state segmentation using a hidden Markov Model [ChromHMM)] and core histone marks: Crimson, flanking TSS; Red, active transcriptional start site (TSS); Dark Green: transcription elongation/transition; Yellow green: transcription enhancer-like; Orange, active-to-weak enhancer. MeDIP: methylated DNA immunoprecipitation, MRE: methylation-sensitive restriction enzyme sequencing, Melanocytes: normal primary penile foreskin melanocytes (UCSF-UBC-USC and UCSF-UBC), Fibroblasts: normal primary penile foreskin fibroblasts (UCSF-UBC-USC and UCSF-UBC), Keratinocytes: normal primary penile foreskin keratinocytes (UCSF-UBC-USC and UCSF-UBC), PBMCs: peripheral blood mononuclear cells (UCSF-UBC-UCD and UCSF UBC), and Lymphocytes:CD19, CD4 and CD8 cells (NIH Epigenomics Roadmap data). TF: transcription factors ChIP-seq (161 factors) from ENCODE with Factorbook Motifs. DNase I: Open chromatin DNase I hypersensitivity clusters in 125 cell types from ENCODE. SNPs rs4660761 and rs7161 are highlighted by colored boxes. Sources and acknowledgements for the UCSC genome, ENCODE, The NIH ROADMAP databases and extracted tracks http://genome.ucsc.edu/goldenPath/credits.html#human_credits.

Mentions: Based on Roadmap and ENCODE data, SNP rs4660761 [A/G] is located in an active promoter region and an unmethylated CpG island (CGI) upstream of the gene ATP6V0B in normal penile foreskin melanocytes, fibroblasts and keratinocytes (Figure 1). The variant G allele of SNP rs4660761 also creates a CpG dinucleotide within the CGI. The DNA region containing SNP rs4660761 maps to DNase I sites and interacts with a number of proteins in ENCODE cell lines including POL2, and the variant has the potential to alter the DNA binding motifs of BRCA1, YY1 and ZBTB33 proteins (Table S4). SNP rs7161, which is in high correlation with SNP rs4660761 (Pearson correlation coefficient, ρ = 0.89), is located in the 3′ UTR region of DPH2 or 5′ of ATP6V0B. SNP rs7161 is reported to locate to an enhancer region with weak H3K4me1 and strong H3K27ac marks in penile foreskin melanocytes using the HaploReg tool (http://www.broadinstitute.org/mammals/haploreg/detail_v2.php?query=&id=rs7161). However, we found no evidence for this enhancer region using Roadmap ChromHMM Primary Core Marks and data from normal melanocytes on the UCSC browser (Figure 1). In K562 and HeLa cells, the DNA region containing SNP rs7161 is strongly enriched for POL2 binding and can also form a chromatin loop structure with the promoter region of the upstream gene IPO13 (Table S4).


Genetic modifiers of neurofibromatosis type 1-associated café-au-lait macule count identified using multi-platform analysis.

Pemov A, Sung H, Hyland PL, Sloan JL, Ruppert SL, Baldwin AM, Boland JF, Bass SE, Lee HJ, Jones KM, Zhang X, NISC Comparative Sequencing ProgramMullikin JC, Widemann BC, Wilson AF, Stewart DR - PLoS Genet. (2014)

Genome Browser (http://genome.ucsc.edu/) image of ATPV0B and DPH2 gene regions on human assembly hg19 based on NIH Epigenomics Roadmap data and ENCODE data [74], [76].The promoter CpG islands (CGIs) of ATPV0B (CGI: 121) is highlighted by a green filled box. Regulatory domains (chromatin state segmentation using a hidden Markov Model [ChromHMM)] and core histone marks: Crimson, flanking TSS; Red, active transcriptional start site (TSS); Dark Green: transcription elongation/transition; Yellow green: transcription enhancer-like; Orange, active-to-weak enhancer. MeDIP: methylated DNA immunoprecipitation, MRE: methylation-sensitive restriction enzyme sequencing, Melanocytes: normal primary penile foreskin melanocytes (UCSF-UBC-USC and UCSF-UBC), Fibroblasts: normal primary penile foreskin fibroblasts (UCSF-UBC-USC and UCSF-UBC), Keratinocytes: normal primary penile foreskin keratinocytes (UCSF-UBC-USC and UCSF-UBC), PBMCs: peripheral blood mononuclear cells (UCSF-UBC-UCD and UCSF UBC), and Lymphocytes:CD19, CD4 and CD8 cells (NIH Epigenomics Roadmap data). TF: transcription factors ChIP-seq (161 factors) from ENCODE with Factorbook Motifs. DNase I: Open chromatin DNase I hypersensitivity clusters in 125 cell types from ENCODE. SNPs rs4660761 and rs7161 are highlighted by colored boxes. Sources and acknowledgements for the UCSC genome, ENCODE, The NIH ROADMAP databases and extracted tracks http://genome.ucsc.edu/goldenPath/credits.html#human_credits.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4199479&req=5

pgen-1004575-g001: Genome Browser (http://genome.ucsc.edu/) image of ATPV0B and DPH2 gene regions on human assembly hg19 based on NIH Epigenomics Roadmap data and ENCODE data [74], [76].The promoter CpG islands (CGIs) of ATPV0B (CGI: 121) is highlighted by a green filled box. Regulatory domains (chromatin state segmentation using a hidden Markov Model [ChromHMM)] and core histone marks: Crimson, flanking TSS; Red, active transcriptional start site (TSS); Dark Green: transcription elongation/transition; Yellow green: transcription enhancer-like; Orange, active-to-weak enhancer. MeDIP: methylated DNA immunoprecipitation, MRE: methylation-sensitive restriction enzyme sequencing, Melanocytes: normal primary penile foreskin melanocytes (UCSF-UBC-USC and UCSF-UBC), Fibroblasts: normal primary penile foreskin fibroblasts (UCSF-UBC-USC and UCSF-UBC), Keratinocytes: normal primary penile foreskin keratinocytes (UCSF-UBC-USC and UCSF-UBC), PBMCs: peripheral blood mononuclear cells (UCSF-UBC-UCD and UCSF UBC), and Lymphocytes:CD19, CD4 and CD8 cells (NIH Epigenomics Roadmap data). TF: transcription factors ChIP-seq (161 factors) from ENCODE with Factorbook Motifs. DNase I: Open chromatin DNase I hypersensitivity clusters in 125 cell types from ENCODE. SNPs rs4660761 and rs7161 are highlighted by colored boxes. Sources and acknowledgements for the UCSC genome, ENCODE, The NIH ROADMAP databases and extracted tracks http://genome.ucsc.edu/goldenPath/credits.html#human_credits.
Mentions: Based on Roadmap and ENCODE data, SNP rs4660761 [A/G] is located in an active promoter region and an unmethylated CpG island (CGI) upstream of the gene ATP6V0B in normal penile foreskin melanocytes, fibroblasts and keratinocytes (Figure 1). The variant G allele of SNP rs4660761 also creates a CpG dinucleotide within the CGI. The DNA region containing SNP rs4660761 maps to DNase I sites and interacts with a number of proteins in ENCODE cell lines including POL2, and the variant has the potential to alter the DNA binding motifs of BRCA1, YY1 and ZBTB33 proteins (Table S4). SNP rs7161, which is in high correlation with SNP rs4660761 (Pearson correlation coefficient, ρ = 0.89), is located in the 3′ UTR region of DPH2 or 5′ of ATP6V0B. SNP rs7161 is reported to locate to an enhancer region with weak H3K4me1 and strong H3K27ac marks in penile foreskin melanocytes using the HaploReg tool (http://www.broadinstitute.org/mammals/haploreg/detail_v2.php?query=&id=rs7161). However, we found no evidence for this enhancer region using Roadmap ChromHMM Primary Core Marks and data from normal melanocytes on the UCSC browser (Figure 1). In K562 and HeLa cells, the DNA region containing SNP rs7161 is strongly enriched for POL2 binding and can also form a chromatin loop structure with the promoter region of the upstream gene IPO13 (Table S4).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus