بررسی تغییرات نوکلئوتیدی ژن LMO1 به عنوان یک تنظیم‌کننده مثبت نسخه‌برداری در بیماران مبتلا به تومورهای مغزی از نوع گلیوبلاستوما

نوع مقاله : مقاله پژوهشی

نویسندگان

1 دانش‌آموخته کارشناسی ارشد ژنتیک، گروه زیست شناسی، دانشگاه یزد، یزد، ایران

2 دانشیار ژنتیک مولکولی، گروه زیست شناسی، دانشگاه یزد، یزد، ایران، (نویسنده مسئول)

3 دانشیار ژنتیک مولکولی، گروه زیست شناسی، دانشگاه یزد، یزد، ایران

4 متخصص بیماری های مغز و اعصاب (نورولوژی)، گروه جراحی مغز و اعصاب، دانشکده پزشکی، دانشگاه علوم پزشکی شهید صدوقی، یزد، ایران

چکیده

مقدمه
گلیوبلاستوما یکی از بدخیم‌ترین تومورهای مغزی است که به‌عنوان تومورهای اولیه اپیتلیال عصبی نیز شناخته می‌شود. تومورهای بدخیم گلیوبلاستوما در حدود 40%-20 موارد از تومورهای مغزی را شامل می‌شوند. ژن LMO1 در موقعیت 11P15.4 قرار دارد و به‌عنوان انکوژن در برخی سرطان‌ها معرفی می‌شود. این مطالعه، برای اولین‌بار در ایران، جهت شناسایی و بررسی ارتباط جهش‌های ژن LMO1 با گلیوبلاستوما ، انجام شده است.
روش کار
در این تحقیق، از تکنیک Touchdown PCR و روش تعیین‌توالی DNA، در 35 نمونه‌ی خون افراد مبتلا به گلیوبلاستومای مولتی‌فرم و 40 نمونه شاهد استفاده ‌شد. همچنین آنالیزهای بیوانفورماتیکی، برای بررسی اثر پاتوژنسیتی تغییرات نوکلئوتیدی در این ژن انجام شد.
نتایج
طی این مطالعه، چهار جهش نقطه‌ای شناسایی شد که دو تا از جهش‌های جدید، بدمعنی بوده و منجر به تغییر اسیدآمینه در یکی از دامین‌های مهم پروتئین می‌شدند (p.M135K و p.N148H) که نشان‌دهنده اهمیت بالقوه بیماریزایی آنها است. نتایج مطالعه ما در چندین پایگاه داده بیوانفورماتیکی، پیش‌بینی کرد که هر دو این جهش‌ها بر عملکرد پروتئین اثرگذار هستند، بگونه‌ای که می‌توانند این دامین را مختل کرده و عملکرد آن را دچار نقص کنند. همچنین، یک تغییر نوکلئوتیدی هم در ناحیه 3'UTR این ژن مشاهده شد (c.*74A>G) که در جایگاه اتصال دو miRNA تنظیمی قرار دارد و پیش‌بینی می‌شود بتواند اتصال این miRNAها به توالی هدف را مختل کند.
نتیجه‌گیری
این یافته‌ها، پیش‌بینی می‌کنند که هرگونه جهش در دامین‌های حساسLIM در ژنLMO1 به طور قابل‌توجهی با بیماریزایی گلیوبلاستومای مولتی‌فرم مرتبط هستند و به احتمال زیاد بر عملکرد این کوفاکتور نسخه‌برداری تاثیر بسزایی دارند.

کلیدواژه‌ها

موضوعات

عنوان مقاله [English]

Investigating Nucleotide Changes of LMO1 Gene as a Positive Regulator of Transcription in Patients with Glioblastoma Brain Tumors

نویسندگان [English]

  • Hadis Mohammadi 1
  • Mohammad Mehdi Heidari 2
  • Mehri Khatami 3
  • Ehsan Ziaeii 4
1 Master's student in Genetics, Department of Biology, Yazd University, Yazd, Iran
2 Associate Professor of Molecular Genetics, Department of Biology, Yazd University, Yazd, Iran, (corresponding author)
3 Associate Professor of Molecular Genetics, Department of Biology, Yazd University, Yazd, Iran
4 Neurology specialist, Department of Neurosurgery, Faculty of Medicine, Shahid Sadougi University of Medical Sciences, Yazd, Iran
چکیده [English]

Introduction
Glioblastoma is one of the most malignant brain tumors, which is also known as primary neuroepithelial tumors. Glioblastoma malignant tumors include 20-40% of brain tumors. The LMO1 gene is located at position 11P15.4 and is introduced as an oncogene in some cancers. This study was conducted for the first time in Iran to identify and investigate the relationship between LMO1 gene mutations and glioblastoma.
method
In this research, the Touchdown PCR technique and DNA sequencing method were used in 35 blood samples of people with glioblastoma multiforme and 40 control samples. Bioinformatics analyses were also performed to investigate the pathogenic effect of nucleotide changes in this gene.
Results
In this study, four point mutations were identified, of which two of the new mutations were misense and led to amino acid changes in one of the important domains of the protein (p.M135K and p.N148H), which indicates their potential pathogenicity. Our results of bioinformatics databases predicted that both of these mutations affect protein function, such that they can disrupt this domain and impair its function. Also, a nucleotide change was observed in the 3'UTR region of this gene (c.*74A>G), which is located at the binding site of two regulatory miRNAs and is expected to disrupt the binding of these miRNAs to the target sequence.
Conclusion
These findings predict that any mutations in the LIM-sensitive domains in the LMO1 gene are significantly related to the pathogenesis of glioblastoma and most likely have a significant impact on the function of this transcriptional cofactor.

کلیدواژه‌ها [English]

  • Brain tumors
  • sequencing
  • Glioblastoma multiform
  • LMO1 gene
  • Touchdown PCR

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مجله دانشکده پزشکی دانشگاه علوم پزشکی مشهد
دوره 67، شماره 4
مهر-آبان1403
مهر و آبان 1403
صفحه 1289-1302

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