CYSTIC FIBROSIS MUTATION SPECTRUM IN NORTH MACEDONIA: A STEP TOWARD PERSONALIZED THERAPY
Terzic M1, Jakimovska M1, Fustik S2, Jakovska T3, Sukarova-Stefanovska E1, Plaseska-Karanfilska D1,*
*Corresponding Author: Professor Dijana Plaseska-Karanfilska, MD, PhD, Research Center for Genetic Engineering and Biotechnology “Georgi D.Efremov,” Macedonian Academy of Sciences and Arts, Av. Krste Misirkov 2, 1000 Skopje, Republic of North Macedonia. Tel: +389-23-235-400/264. E-mail: dijana@manu. edu.mk
page: 35

INTRODUCTION

Cystic fibrosis (CF; MIM #219700) also known as mucoviscidosis, is a well-known disease and the most frequent autosomal recessive disease in the Caucasian population with approximately 1/2500 live births. It is caused by mutations in the CF transmembrane conductance regulator (CFTR/ABCC7; MIM #602421) gene [1], whose dysfunction disrupts the chloride transport in the epithelial cells of the lungs and respiratory system, sweat glands, pancreas, intestine and the vas deferens in men, resulting in various conditions such as: severe chronic pulmonary disease, salt exhaustion, pancreatic insufficiency, liver disease and infertility in men (caused by congenital bilateral aplasia of the vas deferens) [2,3]. The large spectrum of phenotypic characteristics of CF has been shown to involve not only the type of CFTR mutations, but also other genetic factors such as modifier genes and environmental factors. Due to the great clinical variations of CF, the diagnoses of classic CF and non classic CF have emerged. This fact has raised the need to classify the CFTR mutations based on molecular consequences. To the present time, more than 2000 different mutations have been reported in the Cystic Fibrosis Mutation Database (CFMD), most of them being missense, frameshift, splicing and nonsense [Cystic Fibrosis Mutation Database (http://www.genet.sickkids.on.ca); accessed January 2019]. Only a small number of the hundreds of CFTR mutations discovered to date, have been proven to with various clinical presentations. The classification of the CFTR mutations based on their consequences on the CF protein is highly important for the choice of therapy, as well as the predicted outcome. According to their effect on the CFTR protein, the CFTR pathogenic variants can be grouped into six classes. Class I mutations (nonsense, frameshift or splice mutations) produce truncated RNA resulting with absence of CFTR protein at the apical membrane. Class II mutations generate defective processing and maturation of the CFTR protein (it does not fold correctly) and as a result, the CFTR protein fails to reach the apical cell membrane. After producing, the defective CFTR protein is destroyed by the endoplasmic reticulum-associated pathway, and the amount of CFTR protein present on the cell surface is significantly reduced. The most frequent CFTR mutation F508del belongs to this group. For class III mutations, even though the CFTR protein reaches the apical membrane, abnormal regulation of the chloride channel results in impaired gating. Class IV mutations evoke reduced chloride conductance, meaning that CFTR protein reaches apical cell membrane, but the misshaped CFTR pore restricts Cl– flow. In the carriers of class V mutations there is a functional CFTR protein production, however, due to alternative splicing or reduced gene transcription the quantity of the CFTR protein at the cell surface is significantly decreased [4-6]. Class VI mutations are considered to decrease the stability of the functional CFTR protein causing accelerated protein turnover at the cell surface, resulting in unstable flow maintenance of the Cl– ions. The classification of the CFTR mutations based on the effects on CFTR protein production and the amount of residual CFTR protein function helps in establishing the treatment and the decision of which medication may be beneficial for a particular mutation. So far, there are three generally most accepted targeted approaches to enhance the function of CFTR protein. These include: potentiators, that are used for recovering the CFTR protein function at the apical surface of the epithelial cells, disrupted when class III or IV mutations are present; correctors, used for class II mutations, to raise the intracellular processing, allowing higher amounts of CFTR protein to reach the cell surface; and production correctors, which promote the read-through of premature termination codons in mRNA, boosting the production of the CFTR protein in class I CFTR mutations. Moreover, practice has shown that most of the CFTR mutations present multiple molecular defects and should therefore be included in more than just one class of mutations and treated with combined therapy. Furthermore, the treatment of patients with CF requires a multi disciplinary team approach [7]. This study was performed with the intention of characterizing the genotypes of all patients listed in the National Registry of Cystic Fibrosis Patients of the Republic of North Macedonia and to determine the spectrum of pathogenic variants causing CF in our country. This approach allows the implementation of a fast and costeffective first step CFTR mutation screening strategy in our country that is beneficial for faster identification of the causative mutations and giving a definitive diagnosis more rapidly in newly CF suspected individuals, as well as for newborn screening protocols. Furthermore, the knowledge of CFTR mutation classes in CF patients in our country represents a first step toward personalized therapy for CF.



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