POLH – Xeroderma pigmentosum variant type

Xeroderma pigmentosum variant (XP-V) is an autosomal recessive disorder marked by extreme ultraviolet (UV) sensitivity, freckling, and a high predisposition to early-onset skin cancers. XP-V results from biallelic loss-of-function mutations in POLH, which encodes DNA polymerase η responsible for error-free translesion synthesis past UV-induced cyclobutane pyrimidine dimers. Affected individuals typically present in childhood with severe sunburn, freckling, and multiple basal and squamous cell carcinomas (HP:0000982, HP:0000953, HP:0000961).

Genetic evidence for POLH in XP-V includes 21 patients with 16 truncating and missense mutations identified in 2002, establishing the AR inheritance and null allele spectrum ([PMID:11773631]). A cohort of 23 probands from 20 unrelated families revealed 29 POLH mutations—69% truncating—correlating mutation class with clinical severity and confirming segregation with disease ([PMID:24130121]).

Founder effects have been documented: a 3.9 kb deletion spanning exons 9–11 in 16 Tunisian patients from ten consanguineous families ([PMID:24877075]) and a 170-nt exon 10 deletion in an Italian kindred, both resulting in severe protein truncation and absent Polη activity ([PMID:32635709]).

Functional studies demonstrate that Polη deficiency abolishes translesion synthesis and increases UV-induced mutagenesis. Polη-deficient mouse models recapitulate UV sensitivity and skin tumorigenesis ([PMID:15824086], [PMID:25733082]). Rescue experiments show that wild-type but not mutant Polη restores UV tolerance, confirming a loss-of-function mechanism.

The first missense variant c.571A>C (p.Thr191Pro) was shown in vitro and in vivo to abrogate polymerase activity and cause UV sensitivity, upgrading it to likely pathogenic and informing molecular diagnosis ([PMID:38212351]). Additional germline variants (Cys34Trp, Ile147Asn, Arg167Gln) display reduced TLS activity and fail to rescue UV or cisplatin sensitivity in POLH-knockout cells ([PMID:36982269]). Proteasomal degradation of unstable C-terminal Polη variants further contributes to loss of function ([PMID:25766642]).

No credible conflicting evidence has been reported. The cumulative genetic and experimental data spanning over two decades establish a definitive association between POLH and XP-V. Key take-home: comprehensive POLH sequencing and functional validation of variants are essential for accurate XP-V diagnosis, genetic counseling, and potential therapeutic targeting.

References

• Proceedings of the National Academy of Sciences of the United States of America • 2002 • Molecular analysis of mutations in DNA polymerase eta in xeroderma pigmentosum-variant patients. PMID:11773631
• Human Mutation • 2014 • Correlation of phenotype/genotype in a cohort of 23 xeroderma pigmentosum-variant patients reveals 12 new disease-causing POLH mutations. PMID:24130121
• BioMed Research International • 2014 • A founder large deletion mutation in Xeroderma pigmentosum-Variant form in Tunisia: implication for molecular diagnosis and therapy. PMID:24877075
• Giornale italiano di dermatologia e venereologia • 2020 • Rare exon 10 deletion in POLH gene in a family with xeroderma pigmentosum variant correlating with protein expression by immunohistochemistry. PMID:32635709
• The Journal of Experimental Medicine • 2005 • Contribution of DNA polymerase eta to immunoglobulin gene hypermutation in the mouse. PMID:15824086
• DNA Repair • 2015 • UV-induced mutations in epidermal cells of mice defective in DNA polymerase η and/or ι. PMID:25733082
• DNA Repair • 2015 • Aberrant C-terminal domain of polymerase η targets the functional enzyme to the proteosomal degradation pathway. PMID:25766642
• Scientific Reports • 2024 • Homozygous substitution of threonine 191 by proline in polymerase η causes Xeroderma pigmentosum variant. PMID:38212351
• International Journal of Molecular Sciences • 2023 • Identification of Three Human POLH Germline Variants Defective in Complementing the UV- and Cisplatin-Sensitivity of POLH-Deficient Cells. PMID:36982269

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