Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects

Area of Science:

• Genetics
• Molecular Biology
• Hematology

Background:

• Inherited bone marrow failure syndromes (IBMFSs) impair blood cell production.
• Telomere biology disorders like dyskeratosis congenita (DC) involve short telomeres and premature aging.
• Apollo (SNM1B) is a 5'-to-3' DNA exonuclease involved in DNA repair.

Purpose of the Study:

• To identify the genetic cause of a severe IBMFS presenting with DC/HH-like features.
• To investigate the role of Apollo variants in genome stability and telomere maintenance.
• To characterize a novel IBMFS associated with Apollo deficiency.

Main Methods:

• Whole-exome sequencing to identify genetic variants.
• Analysis of patient-derived cells for DNA repair capacity and chromosome stability.
• CRISPR/Cas9 gene editing for functional complementation studies.
• Telomere length and fragility assessment in patient and cell line models.

Main Results:

• Biallelic variants in the Apollo gene (SNM1B) were identified in three unrelated patients with a DC/HH phenotype.
• Patients' cells exhibited spontaneous chromosome instability and impaired DNA repair, which were corrected by gene editing.
• Patient cells showed telomere fragility without global telomere shortening, unlike Apollo knockout cell lines with significant telomere shortening.
• The identified Apollo variants (L142F, L142S) are hypomorphic, retaining partial function.

Conclusions:

• Biallelic Apollo variants cause a novel, severe IBMFS with DC/HH clinical features and normal telomere length.
• Apollo functions as a critical genome caretaker, and its deficiency leads to genomic instability.
• This study expands the spectrum of IBMFS and highlights the importance of Apollo in maintaining genome integrity.