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


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.

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Figure 1: Quantile-quantile plot of observed versus expected P values comparing the burden of new variants in protein-coding genes in familial pulmonary fibrosis cases and controls.
Figure 2: Segregation of heterozygous PARN mutations in familial kindreds with pulmonary fibrosis and the location of the PARN alterations in the different protein domains.
Figure 3: Segregation of heterozygous RTEL1 mutations in familial kindreds with pulmonary fibrosis and the location of the RTEL1 alterations in the different protein domains.
Figure 4: PARN and RTEL1 mutations are associated with short leukocyte telomere lengths.

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We are grateful to the probands and their families for their participation, to A. Young for technical excellence, to S. Nolasco, K. Stephens and G. Wools for their help with blood sample collections, to the Yale Center for Genome Analysis for the generation of exome sequence data, and to the Yale Center for Genome Analysis and the McDermott Center Bioinformatics Core for sequence analysis. The authors acknowledge funding support from the following sources: US National Institutes of Health (NIH) National Center for Advancing Translational Sciences grant UL1TR001105; US NIH grant U54HG006504 (to the Yale Center for Mendelian Genomics); the Howard Hughes Medical Institute (R.P.L.); US NIH grant K12HD068369 (B.D.S.); and US NIH grant R01HL093096 (C.K.G.).

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Authors and Affiliations



C.K.G., C.X. and R.P.L. conceived, designed and directed the study. J.C., S.Z., C.X., W.J., K.B. and S.M. performed genetic analyses. B.D.S., B.H., R.C., M.C. and J.W.S. performed and directed experiments. P.D., F.T., C.E.G., J.W., J.F., C.K., J.K.-T. and Y.M. contributed clinical evaluations. All authors approved the final manuscript and contributed critical revisions to its intellectual content.

Corresponding author

Correspondence to Christine Kim Garcia.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Principal-component analysis of probands and controls.

(a) Principal-component analysis of genotypes from exome data of 99 familial pulmonary fibrosis probands demonstrating clustering with HapMap subjects of European (n = 79), Mexican (n = 19) and African-American (n = 1) ancestry. (b) European controls (n = 2,816) sequenced and analyzed by the Yale Center for Genome Analysis showing clustering with HapMap subjects of European ancestry.

Supplementary Figure 2 Reduced PARN expression of mutant mRNA and protein in EBV-transformed lymphoblastoid cell lines.

(a) PCR amplification and sequencing of genomic DNA validated the presence of the heterozygous c.529C>T (p.Gln177*) mutation in the proband of kindred F70 but not in a control DNA sample. RT-PCR from total cDNA demonstrated a lower level of the Gln177* mutant transcript than the wild-type (WT) transcript from an EBV-transformed lymphoblastoid cell line (LCL) derived from the proband of kindred 70. RT-PCR from cDNA isolated from a control LCL is also shown. Control cell lines were derived from mutation-negative individuals from these kindreds. (b) Immunoblot analysis of PARN and tubulin from LCLs derived from control subjects or from different individuals with the indicated heterozygous PARN mutation. (c) Relative PARN expression of each sample shown in b as quantified by ImageJ. *P < 0.05; n.s., not significant.

Supplementary Figure 3 Sanger sequence electropherograms of PCR products amplified from genomic DNA of probands heterozygous for mutations in PARN and RTEL1.

(a) PARN. (b) RTEL1. Wild-type cDNA sequences are listed above the tracings. Heterozygous mutations are indicated at the positions marked by the arrows. Deleted and inserted bases are boxed and result in an overlap of wild-type and mutant sequences. The predicted translated amino acid sequence of the protein (in single-letter amino acid code) and the exon-intron boundaries are indicated above the cDNA sequence.

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Supplementary Figures 1–3 and Supplementary Tables 1–7. (PDF 516 kb)

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Stuart, B., Choi, J., Zaidi, S. et al. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nat Genet 47, 512–517 (2015).

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