POLD3

Inheritance Pattern: AR

Disease ID:MONDO:0971151

Submitter: ClinGen

POLD3 was first reported in relation to autosomal recessive immunodeficiency in 2023 (Mehawej C et al., PMID: 37030525). Overall, 2 patients from unrelated consanguineous families were found to be homozygous for 2 different missense variants in POLD3, (c.29T>C (p.Ile10Thr), and c.1118A>C (p.Lys373Thr). These individuals show growth restriction, developmental delay, hepatosplenomegaly, erythroderma, and susceptibility to respiratory infections thought to be caused by syndromic primary immunodeficiency. Evidence supporting this gene-disease relationship includes expression studies, functional studies, a rescue model, and a mouse model. Cells from the affected patient had lower POLD3 protein levels than controls, suggesting that the c.29T>C (p.Ile10Thr) missense mutation affected protein levels. POLD1 and POLD2 protein expression levels are also decreased in patient derived cells, indicating that DNA polymerase delta complex stability and function are affected by loss of POLD3 protein expression (PMID: 37030525) Patient fibroblasts show reduced proliferation and lack consistent shape compared to healthy controls, which appears to be caused by cellular arrest at the entry to the S phase, which may be due to a defect in DNA replication. Staining of patient fibroblasts show increased numbers of γ-H2AX foci which further support the idea that the delayed entry into the S phase is due to problems with DNA replication. Staining of CD3+ T cells with the monoclonal Vα7.2 antibody revealed a drastic reduction in the proportion of T cells with a rearranged TRAV1-2 in the patient as compared to healthy controls. Patient T cell receptor β diversity was only 31% of that of a healthy control. This data points to an integral role of POLD3 in maintaining normal T-cell development. Stably overexpressed POLD3 in patient cells with cell cycle delay were rescued through restoration of WT POLD3. These results suggest that the c.1118A>C (p.Lys373Thr variant impacts POLD3 function which causes an impairment in cell cycle progression (PMID: 38099988). Homozygous mice embryos did not survive. 11% of heterozygous mice experienced dwarfism, problems with brain development, and premature death in the first 10 weeks. Given that brain development is dependent on rapid cell proliferation at specific developmental stages, it is indicated that Pold3 heterozygosity limits the capacity for DNA replication(PMID: 27524497). Homozygous humans also show delayed growth/development and possibly shortened lifespans. Adult mice with POLD3 deletion show overall low levels of POLD1-3 in B lymphocytes and depletion of POLD3 in lung, kidney, and liver. Pold3 deletion in adult mice caused a generalized accumulation of DNA damage, leading to a severe pathology and ultimately the death of the animal. Homozygous humans show severely decreased expression of POLD3 in Peripheral Blood Mononuclear Cells and also seem to experience shortened lifespans. FACS analyses showed that whereas overall DNA replication rates were similar in both cell types, a low dose of APH had a bigger impact in reducing BrdU incorporation rates in Pold3 heterozygous cells. In addition, analyses of fork rate progression in stretched DNA fibers confirmed a higher sensitivity of Pold3+/- cells to APH. Altogether, this data reveals that POLD3 is haploinsufficient for stabilizing the Polδ complex, which could explain the severe effects of its deficiency in mammalian cells(PMID: 27524497). In humans, however, POLD3 is haplosufficient and heterozygous humans are considered unaffected. In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.

Inheritance Pattern: AR

Disease ID:MONDO:0971151

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0005365

Submitter: Ambry Genetics