PARN – Dyskeratosis Congenita

Poly(A)-specific ribonuclease (PARN) is implicated in the autosomal recessive telomere biology disorder Dyskeratosis congenita. DC is characterized by defective telomere maintenance leading to bone marrow failure, mucocutaneous abnormalities, and heightened cancer risk.

Genetic studies have identified at least six independent probands from five unrelated families with biallelic PARN variants and autosomal recessive inheritance, confirming segregation of loss-of-function or deleterious missense changes in affected individuals ([PMID:25893598]). Case reports have described compound heterozygous frameshift and missense alleles in children presenting with classical DC features and Hoyeraal-Hreidarsson syndrome, expanding the phenotypic spectrum to include neurological involvement and immunodeficiency ([PMID:39649862]). A young cohort study further identified two juvenile DC patients with compound heterozygous PARN mutations, correlating short telomeres with hematological manifestations ([PMID:32452087]).

The variant spectrum in DC includes both loss-of-function and missense alleles: for example, c.272A>G (p.Tyr91Cys) impairs PARN deadenylase activity in vitro ([PMID:31448843]), whereas frameshift alleles such as c.1749_1750del (p.Glu585fs) truncate critical catalytic domains ([PMID:25893598]). These variants segregate recessively, with unaffected heterozygous carriers displaying normal telomere lengths.

Functional assays demonstrate that PARN deficiency leads to reduced deadenylation of telomerase RNA and H/ACA box snoRNAs, resulting in decreased TERC levels, telomere shortening, p53 activation, and cell-cycle arrest in patient cells ([PMID:25893599]). Knockdown of PARN in human marrow cells and zebrafish models recapitulates bone marrow failure and developmental delay, confirming a causal role in hematopoiesis and telomere maintenance ([PMID:26342108]).

Rescue experiments using PAPD5 inhibition restore telomerase RNA stability and telomere elongation in PARN-deficient human cells, highlighting a potential therapeutic avenue and mechanistic interplay between polyadenylation and deadenylation pathways in DC ([PMID:26950371]).

Collectively, these genetic and experimental data fulfill ClinGen criteria for a Strong gene–disease association. PARN mutations underlie an autosomal recessive form of Dyskeratosis congenita with consistent segregation, a defined variant spectrum, and concordant functional evidence, supporting its clinical utility in diagnostic testing and informing targeted therapeutic strategies.

Key take-home: Biallelic PARN variants cause autosomal recessive DC via impaired deadenylation of telomerase RNA, leading to telomere shortening and bone marrow failure.

References

• The Journal of Clinical Investigation • 2015 • mRNA deadenylation and telomere disease. PMID:25893598
• The Journal of Clinical Investigation • 2015 • Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita. PMID:25893599
• Journal of medical genetics • 2015 • Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN). PMID:26342108
• Journal of clinical laboratory analysis • 2020 • CD8+ T-cell senescence and skewed lymphocyte subsets in young Dyskeratosis Congenita patients with PARN and DKC1 mutations. PMID:32452087
• Annals of medicine and surgery • 2024 • Hoyeraal-Hreidarsson syndrome: a case report of dyskeratosis congenita with a novel PARN gene mutation. PMID:39649862
• Human Mutation • 2019 • From incomplete penetrance with normal telomere length to severe disease and telomere shortening in a family with monoallelic and biallelic PARN pathogenic variants. PMID:31448843

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