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沙特阿拉伯关于由该基因中一个过早终止密码子突变导致的三甲胺尿症的首例报告。

First Report from Saudi Arabia of Trimethylaminuria Caused by a Premature Stop Codon Mutation in the Gene.

作者信息

Alghanem Bandar, Alamri Hassan S, Barhoumi Tlili, Ali Khan Imran, Almuhalhil Khawlah, Aloyouni Essra, Shaibah Hayat, Mashhour Abdullah, Algheribe Shatha, Islam Imadul, Boudjelal Mohamed, Alfadhel Majid

机构信息

Medical Research Core Facility and Platforms, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.

King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.

出版信息

Appl Clin Genet. 2024 Dec 31;17:215-228. doi: 10.2147/TACG.S497959. eCollection 2024.

DOI:10.2147/TACG.S497959
PMID:39758160
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11699836/
Abstract

BACKGROUND

Trimethylaminuria (TMAU) is a rare recessive genetic disorder with limited global prevalence. To date, there have been no official reports of TMAU cases documented in Saudi Arabia.

PURPOSE

In this study, we developed a liquid chromatography-mass spectrometry (LC-MS) method for the analysis of trimethylamine (TMA) and Trimethylamine N-Oxide (TMAO) in urine and plasma samples for the first reported case of TMAU in Saudi Arabia.

PATIENTS AND METHODS

A 41-year-old Saudi man was diagnosed with TMAU in National Guard Hospital. Blood and urine samples were collected to confirm the diagnosis of TMAU. In this study, we have studied LC-MS, cell culture, flow cytometry, adhesion assay and Sanger sequencing analysis. Additionally, in this study, we have selected 5 healthy controls.

RESULTS

The results have revealed elevated TMA levels were present in both urine and plasma samples, while TMAO levels were significantly lower compared to control group. Further, we utilized plasma sample from the TMAU patient as novel model to investigate the potential effect of low TMAO on monocyte and endothelial cell function in vitro. DNA sequencing analysis identified a c.622G >T (p.Glu208*) which creates a premature stop codon in FMO3 gene.

CONCLUSION

Our findings revealed differential responses in monocytes and endothelial cells stimulated with plasma from the TMAU patient compared to plasma from non-TMAU patients. These distinct responses may be key modulators of endothelial function and contributes to vascular damage.

摘要

背景

三甲胺尿症（TMAU）是一种罕见的隐性遗传疾病，全球患病率有限。迄今为止，沙特阿拉伯尚无TMAU病例的官方报告。

目的

在本研究中，我们开发了一种液相色谱-质谱（LC-MS）方法，用于分析尿液和血浆样本中的三甲胺（TMA）和氧化三甲胺（TMAO），以诊断沙特阿拉伯首例TMAU病例。

患者与方法

一名41岁的沙特男子在国民警卫队医院被诊断为TMAU。采集血液和尿液样本以确诊TMAU。在本研究中，我们研究了LC-MS、细胞培养、流式细胞术、黏附试验和桑格测序分析。此外，在本研究中，我们选择了5名健康对照者。

结果

结果显示，尿液和血浆样本中的TMA水平均升高，而TMAO水平与对照组相比显著降低。此外，我们利用TMAU患者的血浆样本作为新模型，体外研究低TMAO对单核细胞和内皮细胞功能的潜在影响。DNA测序分析确定了一个c.622G>T（p.Glu208*）突变，该突变在FMO3基因中产生了一个提前终止密码子。

结论

我们的研究结果显示，与非TMAU患者的血浆相比，TMAU患者的血浆刺激的单核细胞和内皮细胞有不同反应。这些不同反应可能是内皮功能的关键调节因子，并导致血管损伤。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1de/11699836/2c2c6ebfc8f1/TACG-17-215-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1de/11699836/3d1090231e55/TACG-17-215-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1de/11699836/a00b748f539d/TACG-17-215-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1de/11699836/b60f13ef3885/TACG-17-215-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1de/11699836/1fff6aa47081/TACG-17-215-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1de/11699836/18bb7b3b9a80/TACG-17-215-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1de/11699836/8a493f459b43/TACG-17-215-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1de/11699836/5f8f472cf01d/TACG-17-215-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1de/11699836/2c2c6ebfc8f1/TACG-17-215-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1de/11699836/3d1090231e55/TACG-17-215-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1de/11699836/a00b748f539d/TACG-17-215-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1de/11699836/b60f13ef3885/TACG-17-215-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1de/11699836/1fff6aa47081/TACG-17-215-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1de/11699836/18bb7b3b9a80/TACG-17-215-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1de/11699836/8a493f459b43/TACG-17-215-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1de/11699836/5f8f472cf01d/TACG-17-215-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c1de/11699836/2c2c6ebfc8f1/TACG-17-215-g0008.jpg

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本文引用的文献

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Drug Metab Pharmacokinet. 2024 Apr;55:100539. doi: 10.1016/j.dmpk.2023.100539. Epub 2023 Dec 22.
2
Time-dependent specific molecular signatures of inflammation and remodelling are associated with trimethylamine-N-oxide (TMAO)-induced endothelial cell dysfunction.炎症和重构的时变特异性分子特征与三甲胺 N-氧化物（TMAO）诱导的内皮细胞功能障碍有关。
Sci Rep. 2023 Nov 20;13(1):20303. doi: 10.1038/s41598-023-46820-7.
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Simple confirmation methods for rare but impaired variants of human flavin-containing monooxygenase 3 (FMO3) found in an updated genome resource databank.
在更新的基因组资源数据库中发现的人类含黄素单加氧酶3（FMO3）罕见但功能受损变体的简单确认方法。
Drug Metab Pharmacokinet. 2023 Dec;53:100528. doi: 10.1016/j.dmpk.2023.100528. Epub 2023 Aug 23.
4
Modulation of Endothelial Function by TMAO, a Gut Microbiota-Derived Metabolite.三甲胺 N-氧化物（TMAO），一种肠道微生物衍生代谢物，对血管内皮功能的调节作用。
Int J Mol Sci. 2023 Mar 18;24(6):5806. doi: 10.3390/ijms24065806.
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A family study of compound variants of flavin-containing monooxygenase 3 (FMO3) in Japanese subjects found by urinary phenotyping for trimethylaminuria.通过对三甲基胺尿症进行尿表型分析，在日本受试者中发现黄素单加氧酶 3（FMO3）的复合变异的家族研究。
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