Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome

Area of Science:

• Genetics and Molecular Biology
• Immunology
• Human Disease

Background:

• DNA polymerase δ (PolD) is crucial for DNA synthesis and genome stability.
• Omenn syndrome is a severe combined immunodeficiency characterized by T-cell abnormalities.

Purpose of the Study:

• To investigate the genetic basis of Omenn syndrome in a patient with a novel POLD3 mutation.
• To elucidate the functional consequences of the identified POLD3 mutation on DNA replication and cell cycle progression.

Main Methods:

• Whole exome sequencing to identify genetic mutations.
• Molecular and functional analysis of mutant POLD3.
• Assessment of cell cycle progression and DNA damage in patient fibroblasts.
• Rescue experiments using wild-type POLD3 transduction.

Main Results:

• A homozygous missense mutation (c.1118A>C; p.K373T) in POLD3 was identified in the patient.
• Patient fibroblasts displayed impaired S-phase entry and increased double-stranded DNA breaks.
• The cell cycle defect was rescued by wild-type POLD3, confirming the mutation's pathogenicity.

Conclusions:

• Autosomal recessive POLD3 deficiency is a novel cause of profound T-cell deficiency and Omenn syndrome.
• Mutations in POLD3 can lead to severe immunodeficiency and neurological complications.
• This finding expands the genetic landscape of primary immunodeficiencies.