Functional Characterization of TNNC1 Rare Variants Identified in Dilated Cardiomyopathy

ATP-binding cassette subfamily G member 2 (ABCG2) is a physiologically important urate transporter. Accumulating evidence demonstrates that congenital dysfunction of ABCG2 is an important genetic risk factor in gout and hyperuricemia; recent studies suggest the clinical significance of both common and rare variants of ABCG2. However, the effects of rare variants of ABCG2 on the risk of such diseases are not fully understood. Here, using a cohort of 250 Czech individuals of European descent (68 primary hyperuricemia patients and 182 primary gout patients), we examined exonic non-synonymous variants of ABCG2. Based on the results of direct sequencing and database information, we experimentally characterized nine rare variants of ABCG2: R147W (rs372192400), T153M (rs753759474), F373C (rs752626614), T421A (rs199854112), T434M (rs769734146), S476P (not annotated), S572R (rs200894058), D620N (rs34783571), and a three-base deletion K360del (rs750972998). Functional analyses of these rare variants revealed a deficiency in the plasma membrane localization of R147W and S572R, lower levels of cellular proteins of T153M and F373C, and null urate uptake function of T434M and S476P. Accordingly, we newly identified six rare variants of ABCG2 that showed lower or null function. Our findings contribute to deepening the understanding of ABCG2-related gout/hyperuricemia risk and the biochemical characteristics of the ABCG2 protein.

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Identification and functional characterization of KLF5 as a novel disease gene responsible for familial dilated cardiomyopathy

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2019.103827 ◽

2020 ◽

Vol 63 (4) ◽

pp. 103827 ◽

Cited By ~ 2

Author(s):

Ruo-Min Di ◽

Chen-Xi Yang ◽

Cui-Mei Zhao ◽

Fang Yuan ◽

Qi Qiao ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Disease Gene ◽

Functional Characterization ◽

Familial Dilated Cardiomyopathy

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Functional Characterization of 21 Rare Allelic CYP1A2 Variants Identified in a Population of 4773 Japanese Individuals by Assessing Phenacetin O-Deethylation

Journal of Personalized Medicine ◽

10.3390/jpm11080690 ◽

2021 ◽

Vol 11 (8) ◽

pp. 690

Author(s):

Masaki Kumondai ◽

Evelyn Marie Gutiérrez Rico ◽

Eiji Hishinuma ◽

Yuya Nakanishi ◽

Shuki Yamazaki ◽

...

Keyword(s):

Enzymatic Activity ◽

Protein Function ◽

Rare Variants ◽

Functional Characterization ◽

Three Dimensional ◽

Additional Information ◽

Metabolic Reactions ◽

Underlying Mechanisms ◽

Cytochrome Content

Cytochrome P450 1A2 (CYP1A2), which accounts for approximately 13% of the total hepatic cytochrome content, catalyzes the metabolic reactions of approximately 9% of frequently used drugs, including theophylline and olanzapine. Substantial inter-individual differences in enzymatic activity have been observed among patients, which could be caused by genetic polymorphisms. Therefore, we functionally characterized 21 novel CYP1A2 variants identified in 4773 Japanese individuals by determining the kinetic parameters of phenacetin O-deethylation. Our results showed that most of the evaluated variants exhibited decreased or no enzymatic activity, which may be attributed to potential structural alterations. Notably, the Leu98Gln, Gly233Arg, Ser380del Gly454Asp, and Arg457Trp variants did not exhibit quantifiable enzymatic activity. Additionally, three-dimensional (3D) docking analyses were performed to further understand the underlying mechanisms behind variant pharmacokinetics. Our data further suggest that despite mutations occurring on the protein surface, accumulating interactions could result in the impairment of protein function through the destabilization of binding regions and changes in protein folding. Therefore, our findings provide additional information regarding rare CYP1A2 genetic variants and how their underlying effects could clarify discrepancies noted in previous phenotypical studies. This would allow the improvement of personalized therapeutics and highlight the importance of identifying and characterizing rare variants.

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