POLH – Xeroderma Pigmentosum Variant Type

The POLH gene encodes the translesion DNA polymerase η, critical for error-free bypass of UV-induced cyclobutane pyrimidine dimers. Pathogenic biallelic variants in POLH cause the variant subtype of Xeroderma pigmentosum (XP-V), an autosomal recessive photosensitive genodermatosis with elevated skin cancer risk. XP-V patients typically present in childhood with freckle-like pigmentation and cutaneous photosensitivity, often before the appearance of malignancies.

Genetic evidence for POLH-XP association includes at least 42 unrelated probands across diverse populations: three school-age XP-V cases with truncating and exon-skipping mutations (3 probands) (PMID:23651273), a Brazilian cluster of 17 patients sharing two founder alleles (17 probands) (PMID:27664908), and 22 XP-V cases tracing an Iberian haplotype (22 probands) (PMID:32265042). Multi-family segregation in consanguineous pedigrees and population isolates confirms autosomal recessive inheritance and co-segregation of loss-of-function POLH alleles with disease.

The variant spectrum is dominated by truncating, splice-site, and small deletions affecting POLH catalytic and C-terminal domains. A representative pathogenic allele, c.638C>G (p.Ser213Ter), was identified homozygously in a patient with XP-V and early-onset dementia (PMID:32935933). Recurrent founder variants include c.764+1G>A (splice donor) and c.907C>T (p.Arg303Ter) in Brazilian and Spanish cohorts, underscoring population-specific alleles.

Functional studies demonstrate that POLH loss-of-function underlies XP-V: GCN5-deficient cells with reduced POLH transcription exhibit UV hypersensitivity reversible by POLH complementation (PMID:23033487), and Polh–/– mice mirror the human XP-V mutation signature with defective A/T hypermutation in immunoglobulin genes (PMID:15824086). Patient-derived fibroblasts show absent or truncated Pol η expression by immunohistochemistry, correlating with severe UV-induced damage and carcinogenesis.

Additional assays, including ex vivo HEK293T complementation and knock-in studies, confirm that missense variants (e.g., p.Thr191Pro) and frameshifts elude rescue of UV and cisplatin sensitivity, validating a loss-of-function mechanism. Proteasomal degradation of C-terminal mutants further highlights critical domains for stability and nuclear localization.

Collectively, the abundant genetic and experimental concordance establishes a Definitive POLH–XP variant association. POLH variant analysis should be integrated into diagnostic panels for photosensitivity syndromes. Key take-home: Biallelic loss-of-function variants in POLH reliably predict XP-V, guiding early diagnosis, sun-protection strategies, and genetic counseling.

References

• Photodermatology, photoimmunology & photomedicine • 2013 • Three school-age cases of xeroderma pigmentosum variant type. PMID:23651273
• The British journal of dermatology • 2017 • A genetic cluster of patients with variant xeroderma pigmentosum with two different founder mutations. PMID:27664908
• Mutation research. Genetic toxicology and environmental mutagenesis • 2020 • The Iberian legacy into a young genetic xeroderma pigmentosum cluster in central Brazil. PMID:32265042
• Molecular genetics & genomic medicine • 2020 • Novel variants in POLH and TREM2 genes associated with a complex phenotype of xeroderma pigmentosum variant type and early-onset dementia. PMID:32935933
• The Journal of biological chemistry • 2012 • GCN5 protects vertebrate cells against UV-irradiation via controlling gene expression of DNA polymerase η PMID:23033487
• The Journal of experimental medicine • 2005 • Contribution of DNA polymerase eta to immunoglobulin gene hypermutation in the mouse PMID:15824086

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