TY - JOUR
T1 - Synonymous Mutation in DKC1 Causes Telomerase RNA Insufficiency Manifesting as Familial Pulmonary Fibrosis
AU - Gaysinskaya, Valeriya
AU - Stanley, Susan E.
AU - Adam, Soheir
AU - Armanios, Mary
N1 - Funding Information:
Author contributions: V. G. identified the causal mutation, designed and performed the functional studies, and wrote the manuscript with M. A. S. E. S. identified the proband in a screen for patients with low TR levels and performed the initial whole-genome sequence analysis. S. A. analyzed clinical data. M. A. evaluated the family, oversaw the project, and wrote the manuscript with V. G. Financial/nonfinancial disclosures: None declared. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. Other contributions: The authors are grateful to all the patients who participated in this research, and to their family members. The authors are grateful for helpful comments from Armanios laboratory members and for assistance from Nuria Amat with the X-inactivation experiment. The authors appreciate support from the Johns Hopkins Genetic Resource Core Facility team. Additional information: The e-Table can be found in the Supplemental Materials section of the online article. FUNDING/SUPPORT: The authors acknowledge support from NIH grants RO1 CA225027 and RO1 HL119476 and funding from the Williams, Commonwealth, and S&R Foundations. M. A. acknowledges an award in the name of Mrs. P. Godrej. V. G. was supported by NIH T32 HL007534 and F32 HL142207.
Funding Information:
FUNDING/SUPPORT: The authors acknowledge support from NIH grants RO1 CA225027 and RO1 HL119476 and funding from the Williams, Commonwealth, and S&R Foundations. M. A. acknowledges an award in the name of Mrs. P. Godrej. V. G. was supported by NIH T32 HL007534 and F32 HL142207.
Publisher Copyright:
© 2020 American College of Chest Physicians
PY - 2020/12
Y1 - 2020/12
N2 - Background: Idiopathic pulmonary fibrosis (IPF) is the most common of short telomere phenotypes. Familial clustering of IPF is common, but the genetic basis remains unknown in more than one-half of cases. We identified a 65-year-old man with familial IPF, short telomere length, and low telomerase RNA levels. He was diagnosed with a short telomere syndrome after developing hematologic complications post-lung transplantation, but no mutations were identified in a clinical testing pipeline. Research Question: What is the molecular basis underlying the familial IPF and low telomerase RNA levels in this patient? Study Design and Methods: We analyzed whole-genome sequence data and performed functional molecular studies on cells derived from the patient and his family. Results: We identified a previously unreported synonymous variant c.942G>A p.K314K in DKC1, the gene encoding the dyskerin ribonucleoprotein, which is required for telomerase RNA biogenesis. The mutation created a competing de novo exonic splicing enhancer, and the misspliced product was degraded by nonsense-mediated decay causing an overall dyskerin deficiency in mutation carriers. In silico tools identified other rare silent DKC1 variants that warrant functional evaluation if found in patients with short telomere-mediated disease. Interpretation: Our data point to silent mutation in telomere maintenance genes as a mechanism of familial pulmonary fibrosis. In contrast to DKC1 missense mutations, which primarily manifest in children as dyskeratosis congenita, hypomorphic mutations affecting dyskerin levels likely have a predilection to presenting in adults as pulmonary fibrosis.
AB - Background: Idiopathic pulmonary fibrosis (IPF) is the most common of short telomere phenotypes. Familial clustering of IPF is common, but the genetic basis remains unknown in more than one-half of cases. We identified a 65-year-old man with familial IPF, short telomere length, and low telomerase RNA levels. He was diagnosed with a short telomere syndrome after developing hematologic complications post-lung transplantation, but no mutations were identified in a clinical testing pipeline. Research Question: What is the molecular basis underlying the familial IPF and low telomerase RNA levels in this patient? Study Design and Methods: We analyzed whole-genome sequence data and performed functional molecular studies on cells derived from the patient and his family. Results: We identified a previously unreported synonymous variant c.942G>A p.K314K in DKC1, the gene encoding the dyskerin ribonucleoprotein, which is required for telomerase RNA biogenesis. The mutation created a competing de novo exonic splicing enhancer, and the misspliced product was degraded by nonsense-mediated decay causing an overall dyskerin deficiency in mutation carriers. In silico tools identified other rare silent DKC1 variants that warrant functional evaluation if found in patients with short telomere-mediated disease. Interpretation: Our data point to silent mutation in telomere maintenance genes as a mechanism of familial pulmonary fibrosis. In contrast to DKC1 missense mutations, which primarily manifest in children as dyskeratosis congenita, hypomorphic mutations affecting dyskerin levels likely have a predilection to presenting in adults as pulmonary fibrosis.
KW - bone marrow failure
KW - lung transplantation
KW - telomerase
UR - http://www.scopus.com/inward/record.url?scp=85096667488&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85096667488&partnerID=8YFLogxK
U2 - 10.1016/j.chest.2020.07.025
DO - 10.1016/j.chest.2020.07.025
M3 - Article
C2 - 32710892
AN - SCOPUS:85096667488
SN - 0012-3692
VL - 158
SP - 2449
EP - 2457
JO - Diseases of the chest
JF - Diseases of the chest
IS - 6
ER -