Genomic variations of the mevalonate pathway in porokeratosis

eLife

Fei Wu¹  Ningjing Song²  Wenlian Hua³  Chaoying Gu³  Yan Liu⁴  Lianjun Chen⁵  Leihong Xiang⁵  Zhenghua Zhang⁵  Zhen Zhang⁵  Feng Yang⁵  Zhengwen Jiang⁵  Qiong Huang⁵  Jinhua Xu⁵  Zhizhong Zheng⁵  Xinling Bi⁶  Jing Luan⁷  Xuemei Meng⁷  Jun Gu⁷  Shoumin Zhang⁷  Min Fan⁷  Weida Liu⁷  Li Wang⁸  Caihua Li⁹  Ruixiao Ma^1,10  Hua Peng^1,11 

[1] Genesky Biotechnologies Inc, Shanghai, China;Department of Dermatology, Central Hospital of China National Petroleum Corp, Langfang, China;Department of Dermatology, Changhai Hospital, Second Military Medical University, Shanghai, China;Department of Dermatology, Henan Provincial People's Hospital, Zhengzhou, China;Department of Dermatology, Huashan Hospital, Shanghai Medical College of Fudan University, Shanghai, China;Department of Dermatology, Tongji Hospital, Shanghai Jiaotong University, Shanghai, China;Genesky Biotechnologies Inc, Shanghai, China;Institute of Dermatology, Chinese Academy of Medical Sciences, Nanjing, China;School of Life Sciences, Fudan University, Shanghai, China;Shanghai Dermatology Hospital, Shanghai, China;Shenzhen Ruimin Dermatology Hospital, Shenzhen, China;

关键词: porokeratosis;    mevalonate pathway;    genetic testing;   

DOI  :  10.7554/eLife.06322

来源: DOAJ

【 摘 要 】

Porokeratosis (PK) is a heterogeneous group of keratinization disorders. No causal genes except MVK have been identified, even though the disease was linked to several genomic loci. Here, we performed massively parallel sequencing and exonic CNV screening of 12 isoprenoid genes in 134 index PK patients (61 familial and 73 sporadic) and identified causal mutations in three novel genes (PMVK, MVD, and FDPS) in addition to MVK in the mevalonate pathway. Allelic expression imbalance (AEI) assays were performed in 13 lesional tissues. At least one mutation in one of the four genes in the mevalonate pathway was found in 60 (98%) familial and 53 (73%) sporadic patients, which suggests that isoprenoid biosynthesis via the mevalonate pathway may play a role in the pathogenesis of PK. Significantly reduced expression of the wild allele was common in lesional tissues due to gene conversion or some other unknown mechanism. A G-to-A RNA editing was observed in one lesional tissue without AEI. In addition, we observed correlations between the mutations in the four mevalonate pathway genes and clinical manifestations in the PK patients, which might support a new and simplified classification of PK under the guidance of genetic testing.

【 授权许可】

Unknown