NAF1, nuclear assembly factor 1 ribonucleoprotein, encodes a box H/ACA RNA biogenesis factor which intervenes in early assembly steps of human box H/ACA RNPs, including telomerase (PMID: 16601202). NAF1 was firstly reported in relation to pulmonary fibrosis in 2016 (Stanley et al., PMID: 27510903). The report described two frameshift mutations (K319Rfs21 and S329Ifs12 ) in two unrelated females with pulmonary fibrosis and bone marrow failure/ myelodysplasia. The reported variants were segregated with short telomere phenotype and low TR levels. An additional 11 (frameshift, splice site, inframe deletion and missense) variants were reported in the two retrospective cohort studies (Alder et al., (2021) PMID: 34933798 and Zhang et al., (2022) PMID: 36028256) that sequenced patients with Idiopathic Pulmonary Fibrosis (IPF) or IPF/Familial Pulmonary Fibrosis, respectively.
Experimental evidence also supports this gene-disease relationship. Western blot of NAF1 in LCLs derived from mutation carriers detected a lower–molecular weight species similar to those detected by Myc-tagging NAF1 at an isogenic doxycycline-inducible locus in HeLa cells. Immunofluorescence showed a nuclear localization defect of NAF1 in the mutated cells (PMID: 27510903). *Naf1+/− *mice showed decreased TR levels, similar to TR+/− animals. Levels of H/ACA small nucleolar RNAs (snoRNAs) and a small Cajal body RNA were also reduced (PMID: 27510903).
In summary, NAF1 is definitively associated with autosomal dominant pulmonary fibrosis and/or bone marrow failure, Telomere-related. This has been repeatedly demonstrated in both research and diagnostic settings and has been upheld over time.
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