سيستيك فيبروزيز از ژنوتيپ تا فنوتيپ: مقاله مروري

Cystic fibrosis from genotype to phenotype: review article

بيماري سيستيك فيبروزيز (CF)، شايع‌ترين بيماري ژنتيكي اتوزوم مغلوب بوده و با نقص در ژن Cystic fibrosis transmembrane conductance regulator (CFTR) بروز مي‌كند. ژن CFTR يك كانال پروتييني انتقال‌دهنده كلر را به شكل گسترده‌ بر روي سطوح اپي‌تليالي بدن مثل ريه، پانكراس، روده، كبد و پوست بيان مي‌كند. از جمله اثراتي كه ژن معيوب CFTR بر روي پروتيين CFTR مي‌گذارد مي‌توان به نقص در انتقال كلر و كاهش كانال‌هاي كلر بر سطح سلول اشاره كرد. بروز مشكلات ذكر شده در كانال CFTR باعث بسته شدن و عفونت‌هاي مكرر مجاري هوايي، ترشح ناكافي غدد برون‌ريز و بد‌جذبي مواد غذايي مي‌شود. دانشمندان تحقيقات بسياري را در راستاي شناخت بيشتر بيماري CF و راه‌كارهاي بهبود كيفيت زندگي مبتلايان به اين بيماري انجام داده‌اند. عليرغم پيشرفت‌هاي صورت گرفته، به‌دليل پيچيدگي زياد اين بيماري و درگيري‌ گسترده اندام‌هاي مختلف بدن هنوز درمان قطعي براي اين بيماري يافت نشده است. مطالعه و بررسي اين بيماري در تمام سطوح مي‌تواند دريچه‌اي را در يافتن روش‌هاي جديد درماني بگشايد. در چند سال گذشته داروهاي تركيبي براي تصحيح و تقويت عملكرد كانال CFTR معرفي شده كه تاثير به سزايي در كاهش علايم اين بيماري دارند. افزون‌بر دارو، با پيشرفت گسترده روش‌هاي مهندسي ژنتيك و افزايش دقت ابزار‌هاي دستكاري ژنتيك، به‌طور مستقيم ژن معيوب CFTR تصحيح شده و علايم بيماري از بين مي‌رود. اين مقاله با بررسي بيماري CF در حوزه‌ي ژنتيك و تاثير آن بر روي سطوح پروتييني و فيزيولوژيك، تصوير جامعي از اين بيماري را به نمايش گذاشته و به معرفي درمان‌هاي معمول و جديد مي‌پردازد.

Cystic fibrosis (CF) is the most common autosomal recessive genetic disease, which is caused by defection in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CFTR gene codes chloride channels to modulate the homeostasis of epithelial environments. Defective CFTR affects various organs such as the lungs, pancreas, intestine, liver and skin; however, lung impairment is the main reason for mortality in these patients. About 2000 mutations in this gene have been discovered, but nearly 150 mutations lead to serious symptoms. CFTR mutations are classified into six major classes based on phenotypic manifestations such as structural instability of channels, defective processing, malfunctioning chloride-ion transfers and decreased number of chloride channels in the cell membranes. These cause various symptoms such as respiratory infection, intestinal obstruction, pancreatic exocrine insufficiency and malabsorption. Significant improvements in diagnostic tools and methods such as newborn screening, chloride sweat test and gene sequencing have increased the incidence and the prevalence of CF. Enormous studies have also been done on CF recognition and treatment procedures, which have resulted in 30 years of growth in the life expectancy of the patients. Despite the recent achievements, due to the high complexity of this disease and the involvement of various organs, the available treatments are nonpermanent. In the past few years, new combinatorial drugs have been introduced which potentiate and correct CFTR and ameliorate the CF symptoms. Recently, novel genetic engineering methods like CRISPR/Cas9 and TALEN have been utilized to correct the mutated CFTR gene with high accuracy and eradicate the symptoms. Studying this disease at its distinct levels from subcellular to organs could help to find new treatments. Systematic research in finding common attributes between different states of the disease is very beneficial. Interdisciplinary research groups with various expertise in mathematics, biology and engineering could have a great impact on describing the full picture of the disease and development of new treatment strategies. The main part of this article provides a comprehensive overview of cystic fibrosis with emphasis on the key studies on genetics and their effects on cellular and physiological levels. In this work, conventional and new treatment methods have also been discussed.