Xeroderma pigmentosum variant: squamous cell carcinoma of the lower lip harboring exon 11 mutation of POLH

Pereira, Thaís dos Santos Fontes; Castro, Ligia Pereira; Menck, Carlos Frederico Martins; Maia, María Helena Thomaz; Souza, Lucas Lacerda de; Fonseca, Felipe Paiva; Pontes, Hélder Antônio Rebelo; Pontes, Flávia Sirotheau Corrêa; Gomez, Ricardo Santiago

doi:10.1016/j.oooo.2021.03.013

Cited by 4 publications

(2 citation statements)

References 56 publications

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“…The genotype–phenotype relationship in XPV patients remains uncertain. This may be attributed to the fact that the severity of clinical features is not determined by the type and localization of the mutation alone but factors such as the intensity of sun exposure, age, living conditions of the patients and other genetic determinants, e.g., protective polymorphisms might also be involved [ 15 ]. Founder mutations in the POLH gene have been reported in some populations such as Japanese, Korean and Tunisian.…”

Section: Discussionmentioning

confidence: 99%

Identification of Frameshift Variants in POLH Gene Causing Xeroderma Pigmentosum in Two Consanguineous Pakistani Families

Zamani

Khan

Karim

et al. 2022

Genes

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Xeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder characterized by severe sensitivity of skin to sunlight and an increased risk of skin cancer. XP variant (XPV), a milder subtype, is caused by variants in the POLH gene. POLH encodes an error-prone DNA-polymerase eta (pol eta) which performs translesion synthesis past ultraviolet photoproducts. The current study documents the clinical and genetic investigations of two large consanguineous Pakistani families affected with XPV. In family 1, whole exome sequencing (WES) revealed a novel frameshift variant, c.1723dupG (p.(Val575Glyfs*4)), of POLH, which is predicted to cause frameshift and premature truncation of the encoded enzyme. Indeed, our ex vivo studies in HEK293T cells confirmed the truncation of the encoded protein due to the c.1723dupG variant. In family 2, Sanger sequencing of POLH exons, revealed a recurrent nonsense variant, c.437dupA (p.Tyr146*). POLH forms a hetero-tetrameric POLZ complex with REV3L, REV7, POLD2 and POLD3. Next, we performed in silico analysis of POLH and other POLZ complex genes expression in publicly available single cell mRNAseq datasets from adult human healthy and aging skin. We found overlapping expression of POLH, REV3L and POLD2 in multiple cell types including differentiated and undifferentiated keratinocytes, pericytes and melanocytes in healthy skin. However, in aging human skin, POLH expression is reduced in compare to its POLZ complex partners. Insights from our study will facilitate counseling regarding the molecular and phenotypic landscape of POLH-related XPV.

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Section: Discussionmentioning

confidence: 99%

Identification of Frameshift Variants in POLH Gene Causing Xeroderma Pigmentosum in Two Consanguineous Pakistani Families

Zamani

Khan

Karim

et al. 2022

Genes

View full text Add to dashboard Cite

show abstract

“…The main problem in more than 80% of cases is nucleotide excision repair (NER) defect causing a disturbed function of DNA repair harmed by sunlight ultraviolet radiation (1,4). This heightened photosensitivity results in sunburn, pigmentary changes, accelerated skin aging, anda significantly elevated incidence of skin neoplasms, including basal cell carcinoma, squamous cell carcinoma, and melanoma (5,6). Angiosarcomas (ASs) are a group of rare cutaneous and soft tissue sarcomas with a high tumor-related mortality rate that infrequently arise in XP cases (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%