Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN)

Area of Science:

• Molecular Biology
• Genetics
• RNA Metabolism

Background:

• Deadenylation, a critical RNA processing step, is regulated by Poly(A)-specific ribonuclease (PARN).
• The biological significance of germline mutations in PARN remains largely unexplored.
• PARN plays a role in processing both messenger RNAs (mRNAs) and non-coding RNAs.

Observation:

• Mutations in PARN were identified in patients presenting with hematological and neurological symptoms.
• Large monoallelic deletions in PARN were found in four patients with developmental delay or mental illness.
• One patient exhibited a severe neurological phenotype, central hypomyelination, and bone marrow failure, alongside a missense mutation and reduced PARN activity.

Findings:

• PARN deficiency impairs oligoadenylation of specific H/ACA box small nucleolar RNAs.
• PARN-deficient cells display short telomeres and aberrant ribosome profiles, resembling dyskeratosis congenita variants.
• Knockdown of PARN in human marrow cells and zebrafish models demonstrated impaired hematopoiesis.

Implications:

• Monoallelic PARN mutations are implicated in developmental and mental illnesses.
• Biallelic PARN mutations are associated with severe bone marrow failure and central hypomyelination.
• This study establishes a causal link between PARN dysfunction and human diseases, highlighting its critical role in development and hematopoiesis.