Zamani Ghazala Y, Khan Ranjha, Karim Noreen, Ahmed Zubair M, Naeem Muhammad
Medical Genetics Research Laboratory, Department of Biotechnology, Quaid-i-Azam University, Islamabad 45320, Pakistan.
Joint Centre for Human Reproduction and Genetics, Anhui Society for Cell Biology, School of Life Sciences, University of Science and Technology of China, Hefei 230052, China.
Genes (Basel). 2022 Mar 19;13(3):543. doi: 10.3390/genes13030543.
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 gene. 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.(Val575Glyfs4)), of , 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 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 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 and in multiple cell types including differentiated and undifferentiated keratinocytes, pericytes and melanocytes in healthy skin. However, in aging human skin, expression is reduced in compare to its POLZ complex partners. Insights from our study will facilitate counseling regarding the molecular and phenotypic landscape of -related XPV.
着色性干皮病（XP）是一种罕见的常染色体隐性遗传病，其特征是皮肤对阳光极度敏感，患皮肤癌的风险增加。XP变异型（XPV）是一种症状较轻的亚型，由该基因的变异引起。该基因编码易错DNA聚合酶η（pol eta），它能绕过紫外线光产物进行跨损伤合成。本研究记录了两个患有XPV的巴基斯坦近亲大家族的临床和基因研究情况。在家族1中，全外显子组测序（WES）揭示了该基因的一个新的移码变异，即c.1723dupG（p.(Val575Glyfs4)），预计会导致编码酶的移码和过早截断。事实上，我们在HEK293T细胞中的体外研究证实了由于c.1723dupG变异导致编码蛋白的截断。在家族2中，对该基因外显子进行的桑格测序揭示了一个反复出现的无义变异，即c.437dupA（p.Tyr146）。POLH与REV3L、REV7、POLD2和POLD3形成异源四聚体POLZ复合物。接下来，我们对来自成人健康和衰老皮肤的公开单细胞mRNA测序数据集中该基因和其他POLZ复合物基因的表达进行了计算机分析。我们发现在健康皮肤的多种细胞类型中，包括分化和未分化的角质形成细胞、周细胞和黑素细胞，该基因和其他基因有重叠表达。然而，在衰老的人类皮肤中，与它的POLZ复合物伙伴相比，该基因的表达降低。我们研究的见解将有助于就与该基因相关的XPV的分子和表型情况进行咨询。
