Exome sequencing links mutations in <i>PARN</i> and <i>RTEL1</i> with familial pulmonary fibrosis and telomere shortening

Stuart B. D., Choi J., Zaidi S., Xing C., Holohan B., Chen R., ...Daha Fazla

NATURE GENETICS, cilt.47, sa.5, ss.512-517, 2015 (SCI-Expanded) identifier identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 47 Sayı: 5
  • Basım Tarihi: 2015
  • Doi Numarası: 10.1038/ng.3278
  • Dergi Adı: NATURE GENETICS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.512-517
  • Acıbadem Mehmet Ali Aydınlar Üniversitesi Adresli: Hayır

Özet

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 x 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 x 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 similar to 7% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction.