POLA1 – X-linked Reticulate Pigmentary Disorder

POLA1 encodes the catalytic subunit of DNA polymerase α and is essential for initiation of DNA replication. Hemizygous intronic c.1393-354A>G in POLA1 causes X-linked Reticulate Pigmentary Disorder, an X-linked recessive syndrome marked by reticular hyperpigmentation, sterile multiorgan inflammation, and recurrent infections. All reported XLPDR patients harbor this recurrent hypomorphic variant, which induces aberrant splicing and reduced POLA1 expression in patient cells (PMID:33392852; PMID:38165470). Genetic evidence is limited by a single shared variant identified in affected males from at least two unrelated families with segregation in affected individuals.

Functional studies demonstrate that POLA1 deficiency in XLPDR patient blood and fibroblasts leads to a pronounced type I interferon signature and impaired natural killer (NK) cell cytotoxicity in most cases (PMID:33392852). However, a recent report described a patient with concurrent FLG polymorphism showing moderated interferon activation and preserved NK function (PMID:38165470), indicating variable immunophenotypic expressivity. Together, genetic and experimental data support a hypomorphic splice‐defect mechanism causing dysregulated innate immunity in XLPDR. Identification of POLA1 c.1393-354A>G enables molecular diagnosis and guides management of immune dysfunction in affected males.

References

• Journal of clinical immunology • 2021 • Immune Dysfunction in Mendelian Disorders of POLA1 Deficiency. PMID:33392852
• Journal of clinical immunology • 2024 • Filaggrin-Associated Atopic Skin, Eye, Airways, and Gut Disease, Modifying the Presentation of X-Linked Reticular Pigmentary Disorder (XLPDR). PMID:38165470

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