Functional Characterization of a Missense Variant of <i>MLH1</i> Identified in Lynch Syndrome Pedigree

Zaib, Tahir; Zhang, Chunhui; Saleem, Komal; Xu, Lei; Qin, Qian; Wang, Yusi; Ji, Wei; Khan, Hanif; Yu, Hanfei; Zhu, Siqi; Gao, Wei; Huang, Yun; Jia, Xueyuan; Wu, Jie; Song, Haoming; Zhang, Yanqiao; Sun, Wenjing; Fu, Songbin

doi:10.1155/2020/8360841

Cited by 5 publications

(6 citation statements)

References 33 publications

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“…This article has been retracted by Hindawi following an investigation undertaken by the publisher [1]. This investigation has uncovered evidence of one or more of the following indicators of systematic manipulation of the publication process:…”

mentioning

confidence: 99%

Retracted: Functional Characterization of a Missense Variant of MLH1 Identified in Lynch Syndrome Pedigree

2023

Disease Markers

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mentioning

confidence: 99%

Retracted: Functional Characterization of a Missense Variant of MLH1 Identified in Lynch Syndrome Pedigree

2023

Disease Markers

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“…Currently, cheap accessible immunohistochemistry (IHC) technology has been widely used in China to detect MMR protein expressions [ 29 ]. MLH1 missense variant caused the defects in MLH1 and PMS2 proteins expressions [ 19 ], and MSH6 mutation and rarely MSH2 mutation resulted in loss of MSH6 protein expression [ 23 ]. Studies had shown that the sensitivity and specificity of IHC to detect MMR protein mutations were 66.7-90 % and 89-97.3 %, respectively [ 13 , 18 , 23 ].…”

Section: Screening and Diagnosing Criteria And Methodsmentioning

confidence: 99%

Section: Screening and Diagnosing Criteria And Methodsmentioning

confidence: 99%

“…In Pakistan, pathogenic/likely pathogenic MLH1/MSH2 variants account for a large proportion of HNPCC/suspected HNPCC colorectal cancer, mainly including three recurrent variants (MLH1 c.1358dup and c.2041G > A; MSH2 c.943-1G > C) [17]. Moreover, missense mutation was the most common mutation type in Chinese LS [18,19]. Although mutations in MMR genes do not mean that cancer will definitely occur, the related cancer risk in MMR mutation carriers is significantly higher than that of the general population.…”

Section: Ls-related Cancers and Mmr Mutations In Chinamentioning

confidence: 99%

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Overview on population screening for carriers with germline mutations in mismatch repair (MMR) genes in China

Zhang

Chen

2021

Hered Cancer Clin Pract

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DNA mismatch repair (MMR) genes play an important role in maintaining genome stability. Germline mutations in MMR genes disrupt the mismatch repair function and cause genome instability. Carriers with MMR germline mutations are more likely to have MMR deficiency and microsatellite instability (MSI) than non-carriers and are prone to develop colorectal cancer (CRC) and extracolorectal malignancies, known as Lynch syndrome (LS). MMR gene testing for suspected mutation carriers is a reliable method to identify the mutation types and to discover mutation carriers. Given that carriers of MMR germline mutations have a higher risk of LS-related cancers (LS-RC) and a younger age at onset than non-carriers, early surveillance and regular screening of relevant organs of carriers are very important for early detection of related cancers. This review mainly focuses on the general status of MMR carriers, the approaches for early detection and screening, and the surveillance of MMR mutation carriers in China. Population screening of MMR germline mutation carriers in China will be helpful for early detection, early diagnosis and treatment of MMR mutation carriers, which may improve the 5-year survival, and reduce mortality and incidence rate in the long term.

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“…Recently, some studies have also described the absence of protein expression due to the presence of missense gene variants. [36,37] The mechanism accounting for enhanced mRNA degradation in these cases is still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Beneficial effect of ursodeoxycholic acid in patients with acyl‐CoA oxidase 2 (ACOX2) deficiency–associated hypertransaminasemia

et al. 2022

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Background and Aims: A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile acid (BA) side-chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumulation of C27-BAs, mainly 3α,7α,12α-trihydroxy-5β-cholestanoic acid (THCA).We aimed to investigate the prevalence of ACOX2 deficiency-associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration.Methods and Results: Among 33 patients with unexplained hypertransaminasemia from 11 hospitals and 13 of their relatives, seven individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by highperformance liquid chromatography-mass spectrometry. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in two patients and three family members. Two additional nonrelated patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In patients with ADAH, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized aminotransferase levels. Incubation of HuH-7 hepatoma cells with THCA, which was efficiently taken up, but not through BA transporters, increased reactive oxygen species production (flow cytometry), endoplasmic reticulum stress biomarkers (GRP78, CHOP, and XBP1-S/XBP1-U ratio), and BAXα expression (reverse transcription followed by quantitative polymerase chain reaction and immunoblot), whereas cell viability was decreased (tetrazolium salt-based cell viability test). THCA-induced cell toxicity was higher than that of major C24-BAs and was not prevented by UDCA.Fourteen predicted ACOX2 variants were generated (site-directed mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH.Conclusions: Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a noninvasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.

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Functional Characterization of a Missense Variant of MLH1 Identified in Lynch Syndrome Pedigree

Cited by 5 publications

References 33 publications

Retracted: Functional Characterization of a Missense Variant of MLH1 Identified in Lynch Syndrome Pedigree

Retracted: Functional Characterization of a Missense Variant of MLH1 Identified in Lynch Syndrome Pedigree

Overview on population screening for carriers with germline mutations in mismatch repair (MMR) genes in China

Beneficial effect of ursodeoxycholic acid in patients with acyl‐CoA oxidase 2 (ACOX2) deficiency–associated hypertransaminasemia

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