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
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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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