Cystic Fibrosis

CFTR Gene
The CFTR gene was identified in 1989. It is a 230 kb
gene on chromosome 7 encoding a 1480 amino acid
polypeptide, named cystic fibrosis transmembrane
conductance regulator (CFTR), which functions as a
chloride channel in epithelial membrane.
CFTR is a member of superfamily of adenosine
triphosphate
(ATP)-binding
cassette
(ABC)
transporter ATPases, which requires energy of ATP
hydrolysis to actively transport substrates across
cell membrane.
Among the thousands of ABC family members, only
CFTR is an ion channel.

CFTR Gene
CFTR is made up of five domains:
two
membrane-spanning
domains
(MSD1 and MSD2) that form the
chloride ion channel,
two nucleotide-binding domains (NBD1
and NBD2) that bind and hydrolyze ATP,
and a regulatory (R) domain. While
most ABC transporters consist of four
domains

CFTR gene

Fig. 1. Diagram showing CFTR gene and resulting protein

(CFTR, cystic fibrosis transmembrane conductance regulator;
MSD, membrane spanning domain; NBD, nucleotide binding domain;

CTFR Sequence :
Nucleotida

ATC ATC TTT

Amino Acid

ile

ile phe

506

GGT GTT
Gly

508

Deleted in F508

F508 CTFR Sequence :

Nucleotida

ATC ATT

Amino Acid

ile
506

ile

GGT GTT
Gly

Val

Val

CFTR ion channel

CFTR is located primarily in the apical
membrane, where it provides a pathway for
chloride ion (Cl ) movement across
epithelium and regulates the rate of Cl flow.
In addition, CFTR regulates the activity of
epithelial sodium channel (ENaC).
In the sweat duct where electrolytes are
reabsorbed, CFTR function is necessary for
activating ENaC, whereas in respiratory
epithelium where secretion and absorption
occur, CFTR deregulates ENaC activity

CFTR ion Channel

Effects of the CFTR channel on vesicle
trafficking, bicarbonate transport and
the expression of inflammatory
mediators such as
Regulated upon Activation, Normal Tcell Expressed, and Secreted (RANTES),
interleukin-8 (IL-8), interleukin-10 (IL10) and inducible nitric oxide synthase
(iNOS) have also been reported15,16

CF disease
CF adalah penyakit yang diakibatkan mutasi dari
gen CFTR pada long arm kromosom 7 yang
mempengaruhi kanal ion Cl- yang berperan dalam
menjaga keseimbangan ion di permukaan epitel
pada paru dan pankreas.
CF is a fatal autonomic recessive disease in
Caucasian populations
1000 mutasi dapat terjadi pada gen CFTR, yang
paling seering terjadi delesi pada 3 nukleotida DNA
The F508 mutant allele, which encodes a single
amino acid deletion within this 1,480-amino-acidlong protein, is by far the most prevalent allele,
accounting for 66% of mutations worldwide.

CF disease
CFTR is a cAMP-regulated Cl channel that is expressed in
many epithelial tissues.
CFTR, therefore, is positioned as a central regulator of salt
and water transport across multiple epithelia, and its
absence
results
in
organ-specific
ion
transport
abnormalities.
Currently, over 1000 mutations and 200 polymorphic loci in
CFTR have now been identified. These mutations and
polymorphisms confer somewhat variable phenotypes from
classic CF to atypical CF with less severe pulmonary lesions,
pancreatic sufficiency, and normal or borderline sweat Cl
concentration.
As a consequence, reduced net fluid secretion across
affected epithelia is a common theme that leads to ductal
(pancreatic, biliary, bronchiolar, vas deferens) obstruction
and subsequent organ dysfunction (exocrine pancreatic
insufficiency, cirrhosis, bronchiectasis, male infertility).

CFTR Mutation Classes

(i) Class I mutations (null mutations) do not produce the
CFTR protein because of a premature stop signal in the
CFTR DNA.
(ii) Class II mutations do not interfere with the CFTR protein
production, but the protein attains an unstable structure
shortly after translation in the endoplasmic reticulum.
(iii) Class III mutations result in the CFTR protein with
reduced chloride transport on the basis of abnormal
regulation of the chloride channel.
(iv) Class IV mutations partially reduce chloride
conductance through CFTRs.
(v) Class V mutations lead to a severe reduction in the
normal CFTR protein.

CFTR Mutation
By now more than 1,500 different mutations
have been described, but it is important to
understand that the functional consequences of
many of these mutations are poorly understood
and the majority of these mutations are rare.
In fact, less than 10 mutations occur with a
frequency of more than 1%, whereas the most
common mutation worldwide, caused by a
deletion of phenylalanine in position 508
(DF508) is found in approximately 66% of CF
patients.

 CFTR mutations can be grouped into

different
classes
based
on
their
functional consequences on the CFTR
within the cell: CFTR is
either not synthesized (I),
inadequately processed (II),
not regulated (III),
shows abnormal conductance (IV),
has partially defective production (V)
has accelerated degradation (VI)

 The class I, II, and III mutations are

more common and associated with
pancreatic insufficiency,
whereas patients with the less
common class IV, V, and VI mutations
often are pancreatic sufficient.
CFTR is a member of superfamily of
adenosine triphosphate (ATP)-binding
cassette (ABC) transporter ATPases,
which requires energy of ATP
hydrolysis
to
actively
transport
substrates across cell membrane.

Uji CF (Sweat Test)

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