Alternative titles; symbols
HGNC Approved Gene Symbol: PARN
Cytogenetic location: 16p13.12 Genomic coordinates (GRCh38) : 16:14,435,701-14,630,260 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.12 | Dyskeratosis congenita, autosomal recessive 6 | 616353 | Autosomal recessive | 3 |
| Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 4 | 616371 | Autosomal dominant | 3 |
The PARN gene, which belongs to a highly conserved family of exoribonucleases, acts by shortening mRNA poly(A) tail length through the process of deadenylation, thus regulating gene expression (summary by Tummala et al., 2015).
Exonucleolytic degradation of the poly(A) tail is often the first step in the decay of eukaryotic mRNAs. Korner and Wahle (1997) purified the enzyme for deadenylation, PARN, which they named DAN, from calf thymus. Korner et al. (1998) partially sequenced the bovine PARN protein. By searching an EST database with the bovine PARN peptide sequences, they identified a human PARN EST encoding a deduced 639-amino acid protein. The calculated molecular mass of human PARN is 73.5 kD, which was the mass of recombinant PARN expressed in E. coli. The human PARN protein shows sequence similarity to the RNase D family of 3-prime exonucleases, which includes E. coli polymerase I. PARN is a 3-prime exonuclease that prefers poly(A) as the substrate. In an in vitro assay, PARN activity was partially inhibited by PAB1 (604679), resulting in phased shortening of the poly(A) tail of the polyadenylated RNA substrate. The PARN protein is located in both the nucleus and the cytoplasm. It is not stably associated with polysomes or ribosomal subunits. Northern blot analysis detected a 3.1-kb PARN transcript in HeLa cell extracts. The authors noted that the PARN gene is widely expressed.
Korner et al. (1998) noted that the PARN gene maps to chromosome 16.
Dhanraj et al. (2015) demonstrated that knockdown of PARN in human bone marrow CD34+ progenitor cells resulted in smaller colonies and a marked reduction in hematopoietic colony formation compared to controls. Morpholino knockdown of the parn gene in zebrafish resulted in anemia and leukopenia, which was rescued by human PARN.
Using somatic cells and induced pluripotent stem cells (iPSCs) from patients with dyskeratosis congenita with PARN mutations (DKCB6; 616353), Moon et al. (2015) demonstrated that PARN is required for the 3-prime-end maturation of the telomerase RNA component (TERC; 602322). Patient-derived cells as well as immortalized cells in which PARN is disrupted show decreased levels of TERC. Deep sequencing of TERC RNA 3-prime termini showed that PARN is required for removal of posttranscriptionally acquired oligo(A) tails that target nuclear RNAs for degradation. Diminished TERC levels and the increased proportion of oligo(A) forms of TERC are normalized by restoring PARN, which is limiting for TERC maturation in cells. Moon et al. (2015) concluded that their results showed a novel role for PARN in the biogenesis of TERC and provided a mechanism linking PARN mutations to telomere diseases.
Autosomal Recessive Dyskeratosis Congenita 6
In 4 children from 3 unrelated families with autosomal recessive dyskeratosis congenita-6 (DKCB6; 616353) associated with shortened telomeres, Tummala et al. (2015) identified homozygous or compound heterozygous mutations in the PARN gene (604212.0001-604212.0004). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Studies of 1 patient's cells (A383V; 604212.0001) showed reduced deadenylation activity, early DNA damage response with abnormal nuclear p53 (TP53; 191170) expression, cell cycle arrest, and reduced cell viability upon UV treatment. Patient cells showed decreased expression of genes involved in telomere maintenance. The findings suggested a role for PARN in telomere maintenance.
In a 21-year-old woman with a severe form of DKCB6 and neurologic impairment consistent with a diagnosis of Hoyeraal-Hreidarsson syndrome, Dhanraj et al. (2015) identified compound heterozygous mutations in the PARN gene (604212.0009 and 604212.0010). Patient cells showed deficiencies in trimming of specific small nucleolar RNAs (snoRNAs), abnormal ribosomal assembly, abnormally adenylated TERC (602322), and short telomeres (less than the first percentile of controls). The patient had severe bone marrow failure with decreased numbers of CD34+ hematopoietic progenitor cells; patient fibroblasts also showed growth defects. One of the mutant alleles carried an intragenic deletion that was inherited from the mother who had an unspecified mental illness requiring admission to a psychiatric ward. Dhanraj et al. (2015) also reported 2 unrelated children, aged 9 and 10 years, who had de novo monoallelic intragenic PARN deletions associated with global developmental delay and mild dysmorphic features, but no evidence of bone marrow failure. The findings indicated that loss of the PARN gene may be associated with neurologic deficits.
Telomere-Related Pulmonary Fibrosis and/or Bone Marrow Failure Syndrome 4
In affected members of 6 unrelated families with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT4; 616371), Stuart et al. (2015) identified 6 different heterozygous mutations in the PARN gene (see, e.g., 604212.0005-604212.0008). Five of the mutations were truncating, consistent with haploinsufficiency; 1 was a missense mutation. The mutations were found by whole-exome sequencing of 99 probands with a family history of pulmonary fibrosis. Among all families, at least 9 clinically unaffected individuals carried a pathogenic mutation, consistent with incomplete penetrance. There was also evidence of environmental influences, e.g., smoking and occupational factors. Cells from patients with truncating mutations showed reduced protein expression, but additional functional studies were not performed.
In 2 sibs, born of consanguineous parents, with autosomal recessive dyskeratosis congenita-6 (DKCB6; 616353), Tummala et al. (2015) identified a homozygous c.1148C-T transition (SCV000206797) in the PARN gene, resulting in an ala383-to-val (A383V) substitution at a highly conserved residue affecting an alpha helix in nuclease domain-2 (ND2). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 2,500 in-house control samples. Patient lymphoid cells showed that the mutant A383V PARN protein had normal subcellular localization and levels of expression, but had decreased basal deadenylation activity as well as decreased activity after UV exposure and DNA damage compared to wildtype. Patient cells also showed increased cell death after UV exposure, and viable cells were arrested in the G2/M phase, indicating abnormal cell cycle regulation.
In a boy, born of consanguineous parents, with autosomal recessive dyskeratosis congenita-6 (DKCB6; 616353), Tummala et al. (2015) identified a homozygous G-to-T transversion (c.918+1G-T; SCV000206798) in intron 13 of the PARN gene. The mutation resulted in the generation of 2 abnormal transcripts: the skipping of exon 13 causing an in-frame deletion of residues 281-306 (281_306del) in nuclease domain-2 (ND2), and the skipping of exons 13 and 14 resulting in a frameshift and premature termination (Gly281ThrfsTer4). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 2,500 in-house control samples.
In a boy with autosomal recessive dyskeratosis congenita-6 (DKCB6; 616353), Tummala et al. (2015) identified compound heterozygous mutations in the PARN gene: a 1-bp duplication (c.863dupA; SCV000206799), resulting in a frameshift and premature termination (Asn288LysfsTer23), and a 4-bp deletion (c.659+4_659+7delAGTA; 604212.0004) in intron 9, predicted to result in abnormal splicing, the skipping of exon 9, and an in-frame deletion (208_220del) in the R3H domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in 2,500 in-house control samples.
For discussion of the 4-bp deletion in intron 9 of the PARN gene that was found in compound heterozygous state in a patient with autosomal recessive dyskeratosis congenita-6 (DKCB6; 616353) by Tummala et al. (2015), see 604212.0003.
In 2 affected members of a large kindred (F349/F373) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT4; 616371), Stuart et al. (2015) identified a heterozygous A-to-G transition (c.246-2A-G, NM_002582.3) in intron 4 of the PARN gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. Telomere length in the 2 patients was less than 1% of control length. DNA was not available from 3 other affected family members or from 2 family members with an unspecified lung disease, but the presence of the mutation in these individuals was inferred on the basis of location in the pedigree. There were at least 6 unaffected mutation carriers, consistent with incomplete penetrance. Environmental influences such as smoking and occupational factors were also present in those affected.
In 2 affected members of a family (F70) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT4; 616371) and 1 member with an unspecified lung disease, Stuart et al. (2015) identified a heterozygous c.529C-T transition (c.529C-T, NM_002582.3) in the PARN gene, resulting in a gln177-to-ter (Q177X) substitution in the CAF1 ribonuclease domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. DNA was not available from 2 other family members with PFBMFT4 or from 1 other member with an unspecified lung disease, but the presence of the mutation in these individuals was inferred on the basis of location in the pedigree. Telomere length in the proband was less than 1% of control length. There were at least 6 unaffected mutation carriers, consistent with incomplete penetrance. Environmental influences such as smoking and occupational factors were also present in those affected.
In 2 sibs (F416) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT4; 616371), Stuart et al. (2015) identified a heterozygous 1-bp insertion (c.563_564insT, NM_002582.3) in the PARN gene, resulting in a frameshift and premature termination (Ile188IlefsTer7) in the CAF1 ribonuclease domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. DNA was not available from 4 other affected family members. Telomere length in the proband was about 7% of control length. Two affected family members also had premature graying. Environmental influences such as smoking and occupational factors were present in those affected.
In a patient (F432) with telomere-related pulmonary fibrosis without bone marrow failure (PFBMFT4; 616371), Stuart et al. (2015) identified a heterozygous c.1262A-G transition (c.1262A-G, NM_002582.3) in the PARN gene, resulting in a lys421-to-arg (K421R) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases. DNA was not available from an affected cousin of the proband or from 3 other family members with an unspecified lung disease. Telomere length in the proband was less than 1% of control length. Environmental influences such as smoking and occupational factors were present in those affected.
In a 21-year-old woman with a severe form of autosomal recessive dyskeratosis congenita-6 (DKCB6; 616353) and neurologic impairment consistent with a diagnosis of Hoyeraal-Hreidarsson syndrome, Dhanraj et al. (2015) identified compound heterozygous mutations in the PARN gene: a c.1045C-T transition in exon 16, resulting in an arg349-to-trp (R349W) substitution in the nuclease domain, and a 22-kb intragenic deletion (604212.0010) including exons 14 to 18 and resulting in a frameshift and premature termination (Asp307ValfsTer22): Sanger sequencing of the cDNA revealed c.919-1262del344. The truncated protein was predicted to lack essential catalytic parts of the nuclease domain and the RNA recognition motif. The R349W mutation was inherited from the unaffected father, whereas the intragenic deletion was inherited from the mother who had an unspecified mental illness requiring admission to a psychiatric ward. The R349W mutation was not found in over 2,000 control individuals, but it was reported at a low frequency (8.32 x 10(-6)) in the ExAC database. Patient cells showed significantly decreased PARN mRNA levels, suggesting that the deletion resulted in nonsense-mediated mRNA decay. PARN protein levels were also decreased. In vitro functional expression studies showed that the R349W mutant protein had markedly reduced deadenylation activity (about 50%) compared to wildtype. Patient cells showed deficiencies in trimming of specific small nucleolar RNAs (snoRNAs), abnormal ribosomal assembly, abnormally adenylated TERC (602322), and short telomeres (less than the first percentile of controls). The patient had severe bone marrow failure with decreased numbers of CD34+ hematopoietic progenitor cells; patient fibroblasts also showed growth defects.
For discussion of the 22-kb deletion (c.919_1262del344) in the PARN gene that was found in compound heterozygous state in a patient with a severe form of autosomal recessive dyskeratosis congenita-6 (DKCB6; 616353) and neurologic impairment consistent with a diagnosis of Hoyeraal-Hreidarsson syndrome by Dhanraj et al. (2015), see 604212.0009.
Dhanraj, S., Gunja, S. M. R., Deveau, A. P., Nissbeck, M., Boonyawat, B., Coombs, A. J., Renieri, A., Mucciolo, M., Marozza, A., Buoni, S., Turner, L., Li, H., and 9 others. Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN). J. Med. Genet. 52: 738-748, 2015. [PubMed: 26342108] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103292]
Korner, C. G., Wahle, E. Poly(A) tail shortening by a mammalian poly(A)-specific 3-prime-exoribonuclease. J. Biol. Chem. 272: 10448-10456, 1997. [PubMed: 9099687] [Full Text: https://doi.org/10.1074/jbc.272.16.10448]
Korner, C. G., Wormington, M., Muckenthaler, M., Schneider, S., Dehlin, E., Wahle, E. The deadenylating nuclease (DAN) is involved in poly(A) tail removal during the meiotic maturation of Xenopus oocytes. EMBO J. 17: 5427-5437, 1998. [PubMed: 9736620] [Full Text: https://doi.org/10.1093/emboj/17.18.5427]
Moon, D. H., Segal, M., Boyraz, B., Guinan, E., Hofmann, I., Cahan, P., Tai, A. K., Agarwal, S. Poly(A)-specific ribonuclease (PARN) mediates 3-prime-end maturation of the telomerase RNA component. Nature Genet. 47: 1482-1488, 2015. [PubMed: 26482878] [Full Text: https://doi.org/10.1038/ng.3423]
Stuart, B. D., Choi, J., Zaidi, S., Xing, C., Holohan, B., Chen, R., Choi, M., Dhawadkar, P., Torres, F., Girod, C. E., Weissler, J., Fitzgerald, J., and 9 others. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nature Genet. 47: 512-517, 2015. [PubMed: 25848748] [Full Text: https://doi.org/10.1038/ng.3278]
Tummala, H., Walne, A., Collopy, L., Cardoso, S., de la Fuente, J., Lawson, S., Powell, J., Cooper, N., Foster, A., Mohammed, S., Plagnol, V., Vulliamy, T., Dokal, I. Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita. J. Clin. Invest. 125: 2151-2160, 2015. [PubMed: 25893599] [Full Text: https://doi.org/10.1172/JCI78963]