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Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.

Nature genetics | May 28, 2015

Idiopathic pulmonary fibrosis (IPF) is an age-related disease featuring progressive lung scarring. To elucidate the molecular basis of IPF, we performed exome sequencing of familial kindreds with pulmonary fibrosis. Gene burden analysis comparing 78 European cases and 2,816 controls implicated PARN, an exoribonuclease with no previous connection to telomere biology or disease, with five new heterozygous damaging mutations in unrelated cases and none in controls (P = 1.3 × 10(-8)); mutations were shared by all affected relatives (odds in favor of linkage = 4,096:1). RTEL1, an established locus for dyskeratosis congenita, harbored significantly more new damaging and missense variants at conserved residues in cases than in controls (P = 1.6 × 10(-6)). PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic inheritance of short telomeres in family members. Together, these genes explain ~7% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction.

Pubmed ID: 25848748 RIS Download

Mesh terms: Adult | Aged | Aged, 80 and over | Amino Acid Sequence | Case-Control Studies | Cells, Cultured | DNA Helicases | DNA Mutational Analysis | Exome | Exoribonucleases | Female | Genetic Association Studies | Genetic Predisposition to Disease | Humans | Idiopathic Pulmonary Fibrosis | Leukocytes | Lod Score | Male | Middle Aged | Molecular Sequence Data | Pedigree | Telomere | Telomere Shortening

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Associated grants

  • Agency: NCATS NIH HHS, Id: UL1 TR001105
  • Agency: NIEHS NIH HHS, Id: P30 ES005605
  • Agency: NHLBI NIH HHS, Id: R01 HL093096
  • Agency: NHGRI NIH HHS, Id: U54HG006504
  • Agency: NHGRI NIH HHS, Id: U54 HG006504
  • Agency: NHLBI NIH HHS, Id: R01HL093096
  • Agency: NICHD NIH HHS, Id: K12HD068369
  • Agency: NCATS NIH HHS, Id: UL1TR001105
  • Agency: NIGMS NIH HHS, Id: T32 GM007205
  • Agency: Howard Hughes Medical Institute, Id: P30 DK054759
  • Agency: NIDDK NIH HHS, Id: P30 CA016359
  • Agency: NCI NIH HHS, Id: K12 HD068369
  • Agency: NICHD NIH HHS, Id:

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Cold Spring Harbor Laboratory

Non profit, private research and education institution that performs molecular and genetic research used to generate methods for better diagnostics and treatments for cancer and neurological diseases. Research of cancer causing genes and their respective signaling pathways, mutations and structural variations of the human genome that could cause neurodevelopmental and neurodegenerative illnesses such as autism, schizophrenia, and Alzheimer's and Parkinson's diseases and also research in plant genetics and quantitative biology.

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SAMTOOLS

Software tool for manipulating alignments in SAM format for storing nucleotide sequence alignment, including sorting, merging, indexing and generating alignments in per position format. Parts that are relevant to genetic analysis include SNP and indel callings.

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International HapMap Project

THIS RESOURCE IS NO LONGER IN SERVICE, documented August 22, 2016. A multi-country collaboration among scientists and funding agencies to develop a public resource where genetic similarities and differences in human beings are identified and catalogued. Using this information, researchers will be able to find genes that affect health, disease, and individual responses to medications and environmental factors. All of the information generated by the Project will be released into the public domain. Their goal is to compare the genetic sequences of different individuals to identify chromosomal regions where genetic variants are shared. Public and private organizations in six countries are participating in the International HapMap Project. Data generated by the Project can be downloaded with minimal constraints. HapMap project related data, software, and documentation include: bulk data on genotypes, frequencies, LD data, phasing data, allocated SNPs, recombination rates and hotspots, SNP assays, Perlegen amplicons, raw data, inferred genotypes, and mitochondrial and chrY haplogroups; Generic Genome Browser software; protocols and information on assay design, genotyping and other protocols used in the project; and documentation of samples/individuals and the XML format used in the project.

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