Complex ATP7B mutation patterns in Wilson disease and evaluation of a yeast model for functional analysis of variants
| Autor: | Xiaoming Wang, Xinyan Zhao, Sujun Zheng, Siyu Jia, Jian Huang, Jidong Jia, Anjian Xu, Yongpeng Chen, Hong You, Jia Shang, Wei Zhang, Hejing Wang, Tingxia Lv, Xiaojuan Ou, Zhen Wu, Xiaojin Li, Yu Wang, Yanmeng Li, Qianyi Wang, Weijia Duan, Li-Ying Sun, Bei Zhang, Mei Liu, Wei Jiang, Yuemin Nan, Donghu Zhou |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male Adolescent Genotype Gene Expression Disease Biology Compound heterozygosity Frameshift mutation 03 medical and health sciences Young Adult Hepatolenticular Degeneration Yeasts Genetics medicine Humans Genetic Predisposition to Disease Allele Child Genetics (clinical) 030304 developmental biology 0303 health sciences 030305 genetics & heredity Genetic disorder Genetic Variation Middle Aged medicine.disease Phenotype Pedigree Copper-Transporting ATPases Child Preschool Mutation (genetic algorithm) RNA splicing Mutation Female |
| Zdroj: | Human mutation. 40(5) |
| ISSN: | 1098-1004 |
| Popis: | Wilson disease (WD) is a rare autosomal recessive genetic disorder that is associated with various mutations in the ATP7B gene. Although ATP7B variants are frequently identified, the exact mutation patterns remain unknown because of the absence of pedigree studies, and the functional consequences of individual ATP7B variants remain to be clarified. In this study, we recruited 65 clinically diagnosed WD patients from 60 unrelated families. Pedigree analysis showed that besides several ATP7B homozygous variants (8/65, 12.3%), compound heterozygous variants (43/65, 66.2%) were present in the majority of WD patients. There were 20% of the patients had one (12/65, 18.5%) or multiple (1/65, 1.5%) variants in only a single allele, characterized by a high ratio of splicing or frameshift variants. Nine ATP7B variants were cloned into the pAG426GPD yeast expression vector to evaluate their functional consequences, and the results suggested different degrees of functional disruption from mild or uncertain to severe, consistent with the corresponding phenotypes. Our study revealed the complex ATP7B mutation patterns in WD patients and the applicability of a yeast model system to the evaluation of the functional consequences of ATP7B variants, which is essential for WD cases that are difficult to interpret. |
| Databáze: | OpenAIRE |
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