Alternative titles; symbols
HGNC Approved Gene Symbol: NAF1
Cytogenetic location: 4q32.2 Genomic coordinates (GRCh38) : 4:163,103,929-163,166,890 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q32.2 | Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7 | 620365 | Autosomal dominant | 3 |
Telomerase is a ribonucleoprotein particle (RNP) that catalyzes the addition of repetitive DNA sequences to telomeres. It consists of an RNA component (TR, or TERC; 602322), a reverse transcriptase (TERT; 187270), and several proteins that it shares with box H/ACA small Cajal body RNPs (scaRNPs) and small nucleolar RNPs (snoRNPs). NAF1 is involved in early assembly of box H/ACA RNPs, including telomerase (Hoareau-Aveilla et al., 2006).
Using immunohistochemical analysis, Hoareau-Aveilla et al. (2006) found that human NAF1 localized to nucleoplasmic foci in human and mouse cell lines. NAF1 was excluded from nucleoli and Cajal bodies.
Stanley et al. (2016) reported that the deduced 494-amino acid human NAF1 protein has a central GAR1 (NOLA1; 606468) homology domain, followed by a nuclear localization signal, an RE/RS domain, and P+Q domain.
Hartz (2018) mapped the NAF1 gene to chromosome 4q32.2 based on an alignment of the NAF1 sequence (GenBank BC008207) with the genomic sequence (GRCh38).
Stanley et al. (2016) mapped the mouse Naf1 gene to chromosome 8B3.3.
Human telomerase includes the RNA component TR (TERC; 602322) and protein subunits that are shared with small nucleolar RNPs, including dyskerin (SKC1 300126), GAR1, NHP2 (606470), and NOP10 (606471).
Hoareau-Aveilla et al. (2006) found that deletion of yeast Naf1 caused a growth defect concomitant with loss of box H/ACA RNP protein subunits and box H/ACA snoRNAs. Expression of human NAF1 complemented the growth defect and loss of snoRNPs in Naf1-deleted yeast. Immunoprecipitation analysis showed that human NAF1 interacted with protein and RNA components of snoRNPs, scaRNPs, and telomerase, including dyskerin (SKC1; 300126) and NOP10 (606471). Knockdown of NAF1 via small interfering RNA (siRNA) reduced HeLa cell content of dyskerin, NOP10, and box H/ACA snoRNAs, scaRNAs, and TR.
Stanley et al. (2016) confirmed that knockdown of NAF1 in HeLa cells via siRNA destabilized TR and decreased its cellular content.
In 4 affected members of a 2-generation family (JH1) with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-7 (PFBMFT7; 620365), Stanley et al. (2016) identified a heterozygous frameshift mutation in the NAF1 gene (617868.0001). The mutation, which was found by whole-genome sequencing followed by a candidate search of telomerase RNA biogenesis genes, segregated with the disorder in the family. Subsequent direct sequencing of the NAF1 gene among another cohort of patients with pulmonary fibrosis identified 1 woman (JH2) who carried a different heterozygous frameshift mutation (617868.0002). The patients had short telomere length and low telomerase RNA levels (TERC; 602322). In vitro functional studies indicated that the mutations caused a partial or complete loss of NAF1 function and did not act in a dominant-negative manner. The authors concluded that NAF1 haploinsufficiency disturbs telomere length homeostasis by decreasing the levels of TERC. Altogether, NAF1 mutations were found in 2 (7%) of 30 patients with pulmonary fibrosis.
Stanley et al. (2016) found that Naf1 +/- mice were normal but had half the level of telomerase RNA and reduced content of box H/ACA snoRNAs and scaRNAs compared with wildtype animals. Ribosomal RNA pseudouridylation was preserved. Interbreeding Naf1 +/- animals yielded no Naf1 -/- embryos, with loss prior to embryonic day 8.5.
In 4 affected members of a 2-generation family (JH1) with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-7 (PFBMFT7; 620365), Stanley et al. (2016) identified a heterozygous 1-bp insertion (c.984insA, NM_138386.2) in exon 7 of the NAF1 gene, resulting in a frameshift and premature termination (Ser329IlefsTer12). The mutation, which was found by whole-genome sequencing, segregated with the disorder in the family. It was not present in 9,006 individuals in public databases or in 134 in-house controls. Patient cells showed about 50% decreased levels of full-length NAF1 protein and the presence of a truncated protein. The mutant did not suppress TERC (602322) levels when overexpressed in HeLa cells, indicating that it did not cause a dominant-negative effect. The mutant was able to rescue TERC levels after NAF1 knockdown in HeLa cells, suggesting that it retains some function and is likely a hypomorphic allele. Further in vitro studies showed that a homozygous S329fs mutant clone caused significantly decreased TERC levels, indicating that the mutation has detrimental functional effects. The S329fs mutation interrupted part of the nuclear localization signal, and the truncated protein localized to the cytoplasm.
In a 57-year-old woman (JH2) with telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-7 (PFBMFT7; 620365), Stanley et al. (2016) identified a heterozygous 2-bp deletion (c.956_957delAA) in exon 7 of the NAF1 gene, resulting in a frameshift and premature termination (Lys319ArgfsTer21). The mutation, which was found by whole-genome sequencing, segregated with the disorder in the family. It was not present in 9,006 individuals in public databases or in 134 in-house controls. She had no family history of the disorder, and the deceased parents were not sequenced. Expression of the mutation into HeLa cells showed presence of a truncated protein that did not reduce TERC (602322) levels, indicating that it did not cause a dominant-negative effect. However, K319fs was unable to rescue low TERC levels in NAF1-null HeLa cells, consistent with a loss of function. The mutation disrupted the nuclear localization signal, and the truncated protein localized to the cytoplasm.
Hartz, P. A. Personal Communication. Baltimore, Md. 2/7/2018.
Hoareau-Aveilla, C., Bonoli, M., Caizergues-Ferrer, M., Henry, Y. hNaf1 is required for accumulation of human box H/ACA snoRNPs, scaRNPs, and telomerase. RNA 12: 832-840, 2006. [PubMed: 16601202] [Full Text: https://doi.org/10.1261/rna.2344106]
Stanley, S. E., Gable, D. L., Wagner, C. L., Carlile, T. M., Hanumanthu, V. S., Podlevsky, J. D., Khalil, S. E., DeZern, A. E., Rojas-Duran, M. F., Applegate, C. D., Alder, J. K., Parry, E. M., Gilbert, W. V., Armanios, M. Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis-emphysema. Sci. Transl. Med. 8: 351ra107, 2016. Note: Electronic Article. [PubMed: 27510903] [Full Text: https://doi.org/10.1126/scitranslmed.aaf7837]