Abstract
We provide first evidence that a heterozygous NOP10 mutation (c.17A>G,p.Tyr6Cys) identified in a large family co-segregates with adult-onset familial PF and predisposes to short telomere syndrome (familial PF, liver, haematological diseases) http://bit.ly/2wvXsUd
To the Editor:
Germline telomere-related gene mutations are associated with familial pulmonary fibrosis and lead to short telomere syndrome [1, 2]. Most of the short telomere syndrome-related genes, such as TERT, TERC, DKC1, TINF2, NHP2 and NOP10, were identified in dyskeratosis congenita patients with early onset mucocutaneous manifestations and/or bone marrow failure [3]. The telomerase complex includes TERT, the TERC RNA and DKC1. NOP10, along with DKC1, NHP2 and GAR1, is essential for TERC stability and telomere maintenance [4]. Homozygous NOP10 mutation (c.100C>T, p.Arg34Trp) has been reported only once in a consanguineous family with autosomic recessive dyskeratosis congenita without pulmonary fibrosis [5]. Moreover, the p.Arg34Trp NOP10 mutation caused telomere shortening in homozygous and heterozygous carriers [5]. Here we provide evidence that a heterozygous NOP10 mutation (c.17A>G,p.Tyr6Cys) identified in a large family co-segregates with adult-onset familial pulmonary fibrosis.
The proband (II.1), a 68-year-old non-smoker female, was diagnosed with pulmonary fibrosis at the age of 66 years (figure 1a and b). Two deceased, a brother (II.2) and sister (II.6), and one alive sister (II.7) were also diagnosed with pulmonary fibrosis (figure 1c). Another brother (II.4) and his son (III.5) died from leukaemia while one of the sons of the proband (III.2) had long-term leukopenia. The deceased father of the proband (I.1) was diagnosed with non-alcoholic liver cirrhosis (figure 1a). Mucocutaneous manifestations were not observed upon examination in this family.
We identified by whole exome sequencing in the proband (II.1) a heterozygous pathogenic missense mutation in NOP10 (NM_ 018648) c.17A>G,p.Tyr6Cys according to international recommendations (figure 1a) [6]. No other rare variants predicted to be deleterious were found in whole exome data from the proband in the other genes linked to short telomere syndrome (TERT, TERC, DKC1, TINF2, RTEL1, PARN, NAF1, ACD, NHP2, WRAP53, SHQ1 and ZCCHC8) [7–9]. The variation is absent in 140 000 individuals from the gnomAD database. The mutated adenine is conserved at a genomic level (GERP=5). The in silico tools Polyphen 2 and CADD predicted a deleterious impact of the amino acid change p.Tyr6Cys with scores of 1 and 24, respectively, reflecting high conservation at a protein level. Flow cytometry and FISH (flowFISH) revealed that telomere length of the proband were shorter than the first percentile [6]. It was not possible to organise flowFISH analysis for all individuals of this family. Thus, telomere length for the individuals II.1, II.7, III.1 and III.2 was also measured through telomeric restriction fragment assay [9] at 7.4 kb, 6.3 kb, 8.5 kb and 8.6 kb, respectively. Telomere length for the individuals III.1 and III.2 were found to be shorter relative to the mother's telomere length [2]. The fact that non-carrier (III.1) and carrier (III.2) brother were found to have the same range of telomere length could be attributed to the “heritability” of telomere length and evocates epigenetic inheritance [10]. The variation co-segregated with pulmonary fibrosis (II.1 II.7; and the obligate carrier II.6) and leukopenia (III.2). Incomplete penetrance observed for the asymptomatic niece (III.8) carrier of the mutation is frequently observed in short telomere syndrome at the age of 50 years (figure 1a) [2].
Analysis of the human NOP10 protein three-dimensional structure demonstrated that the mutated amino acid Tyr6 is buried with the small, N-terminal globular, ribbon domain of NOP10, which is in close contact with Dyskerin DKC1 (Cbf5 in the archaeal complex) (figure 1d). Hence it is likely that it plays a critical role for the stability of the domain as well as for the integrity of the DKC1/NHP2/GAR1/NOP10 complex [11–14].
In this family, the combination of familial pulmonary fibrosis, the extra-pulmonary manifestations, including haematological and liver disease, the significant telomere shortening, and the genetic anticipation (II.4: 61 years; III.4 onset at 26 years/II.1: 66 years; III.2: 43 years) strongly evokes a diagnosis of telomeropathy [15]. This is supported by the identification of a monoallelic rare variation predicted to be deleterious in the NOP10 telomere-related gene that co-segregates with disease. Collectively, these results provide the first evidence that mono-allelic NOP10 mutation can predispose to short telomere syndrome (familial pulmonary fibrosis, liver and haematological diseases).
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Footnotes
Conflict of interest: C. Kannengiesser has nothing to disclose.
Conflict of interest: E.D. Manali reports personal fees and non-financial support from Boehringer Ingelheim and Roche, during the conduct of the study.
Conflict of interest: P. Revy has nothing to disclose.
Conflict of interest: I. Callebaut has nothing to disclose.
Conflict of interest: I. Ba has nothing to disclose.
Conflict of interest: A. Borgel has nothing to disclose.
Conflict of interest: C. Oudin has nothing to disclose.
Conflict of interest: A. Haritou has nothing to disclose.
Conflict of interest: L. Kolilekas has nothing to disclose.
Conflict of interest: K. Malagari has nothing to disclose.
Conflict of interest: R. Borie reports grants and personal fees from Boehringer Ingelheim and Roche, personal fees from Savapharma, outside the submitted work.
Conflict of interest: E. Lainey has nothing to disclose.
Conflict of interest: C. Boileau has nothing to disclose.
Conflict of interest: B. Crestani reports personal fees from AstraZeneca and Sanofi, grants, personal fees and non-financial support from Boehringer Ingelheim and Roche, personal fees and non-financial support from BMS, outside the submitted work.
Conflict of interest: S.A. Papiris reports personal fees and non-financial support from Boehringer Ingelheim and Roche, during the conduct of the study.
Support statement: This work (exome sequencing) was supported by a grant “FPI-SPC” from Université Sorbonne Paris Cité (B. Crestani) and the Chancellerie des Universités de Paris (legs Poix; C. Kannengiesser). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received December 21, 2019.
- Accepted February 10, 2020.
- Copyright ©ERS 2020