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A Quick Guide to the
G542X
Mutation
CFTR
SCIENCE
© 2016 Vertex Pharmaceuticals Incorporated | VXR-HQ-02-00045a(1) | 03/2016
Loss of CFTR activity is the underlying cause of
cystic fibrosis (CF)1
Spectrum of Phenotypes Associated
With Total CFTR Activity1,2
•P
eople with 2 CFTR mutations
resulting in loss of CFTR activity
generally have a CF phenotype,
which may include1-3,6
100%
Clinical Phenotype
No CF Disease
–E
levated sweat chloride
(>60 mmol/L)
– Pancreatic insufficiency
Individuals with 2 normal alleles and CFTR mutation carriers
– CBAVD­a
– Lung function decline over time
Total CFTR
Activity
CFTR-related
Disorders
% of Normal
Clinical entities associated with CFTR dysfunction
that do not fulfill diagnostic criteria for CF, e.g., CBAVD,
acute recurrent or chronic pancreatitis and bronchiectasis
Some CFTR mutations
result in residual or
partial CFTR activity3-5
0%
Cystic Fibrosis
0%
Total CFTR
Activity
100%
–P
seudomonas aeruginosa
colonization
Some CFTR mutations
result in little to no
CFTR activity3-5
0%
100%
Typical phenotype: sinopulmonary disease, sweat
chloride >60 mmol/L,
insufficiency,
Totalpancreatic
CFTR
Activity
appearing early in life.
In some patients, progression
of disease is delayed or not all features are present
CBAVD, congenital bilateral absence of the vas deferens.
a
References: 1. Davis PB et al. Am J Respir Crit Care Med. 1996;154(5):1229-1256. 2. Rowe SM et al. Proc Am Thorac Soc. 2007;4(4):387-398.
3. Zielenski J. Respiration. 2000;67(2):117-133. 4. Sheppard DN et al. Nature. 1993;362(6416):160-164. 5. Welsh MJ, Smith AE. Cell. 1993;73(7):
1251-1254. 6. Castellani C et al. J Cyst Fibros. 2008;7(3):179-196.
2
Levels of CFTR activity affect survival in CF1
Survival Curves by CFTR Activity During a 10-Year Follow-Up
(1993-2002) of Patients From the US CFF Registrya
Survival Probability
1.00
0.75
n=1126
0.50
n=14,525
0.25
Residual CFTR activity (Class IV, V): R117H, R334W, R347P, 3849+10KbC–›T, 2789+5G–›A, A455E
Severely reduced CFTR activity (Class I, II, III): G542X, R553X, W1282X, R1162X, 621-IG–›T,
1717-1G–›A, 1078delT, 3659delC, I507del, N1303K, S549N, G85E, F508del, G551D, R560T
0.00
0
10
20
30
40
50
Risk Time (Age)
Adapted with permission from McKone EF et al. Chest. 2006;130(5):1441-1447.
This survival curve represents population-based outcomes.1 Individual outcomes
in cystic fibrosis are variable.
aData are from a retrospective study of patients enrolled in the Cystic Fibrosis Foundation patient registry measuring risk of death over a 10-year observation period
from 1993 to 2002. Patients were grouped as having a high-risk or low-risk genotype based on the functional effects of their class of CFTR mutation on phenotype
and mortality. Patients having a Class I, II, or III mutation on both alleles were considered high-risk, while patients having at least 1 Class IV or V mutation were
categorized as low-risk. A total of 15,651 patients had a CFTR genotype of a known functional class; 14,525 (93%) had a high-risk CFTR genotype and 1126 (7%)
had a low-risk CFTR genotype.1
References: 1. McKone EF et al. Chest. 2006;130(5):1441-1447. 2. The World Bank. http://data.worldbank.org/indicator/SP.DYN.LE00.IN?page=2. Accessed
November 12, 2015. 3. MacKenzie T et al. Ann Int Med. 2014;161:233-241.
•L
ife expectancy in Western
countries (general population
born in 2000) is ~79 years2
•B
etween 1993 and 2002,
median survival for US patients
with genotypes associated with
little to no CFTR activity was
36.3 years (95% CI, 35.5 to
37.6 years), while median
survival for those having
genotypes associated with
residual CFTR activity was
50 years (95% CI, 47.1 to
55.9 years)1
– In this study, patients
with the G542X mutation
(Class I) were part of
the severely reduced CFTR
activity group
•M
ore recent US data (2000-2010)
suggest median survival across
genotypes continues to improve3
3
G542X is the second most common CFTR mutation
in the world1
Prevalence of the G542X Mutation in Patients
With Cystic Fibrosis (% of Patients With at Least 1 Allele)
• In the CFTR2 global
database, ~4% of patients
with CF have at least 1 copy
of the G542X mutation1
Additional sources report
frequency of the G542X mutation
on CF alleles
Can2: 4%
US3: 5%
Brazil4:
4%
Europe:
Belgium5: 5%
UK6: 4%
France7: 3%
Germany8: 2%
Netherlands9: 2%
Ireland10: 2%
Aus11: 3%
New Zealand12: 3%
References: 1. US CF Foundation, Johns Hopkins University, The Hospital for Sick Children. The Clinical and Functional TRanslation of CFTR (CFTR2).
http://www.cftr2.org. Accessed November 12, 2015. 2. Cystic Fibrosis Canada. Canadian Cystic Fibrosis Registry 2013 Annual Report. Toronto, ON: Cystic Fibrosis
Canada; 2015. 3. Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry 2013 Annual Data Report. Bethesda, MD. © 2014; Cystic Fibrosis Foundation.
4. The Brazilian Cystic Fibrosis Study Group. Brazilian Cystic Fibrosis Patient Registry. 2012 Annual Report. 5. Belgisch Mucoviscidose Register – Registre Belge de la
Mucoviscidose. The Belgian Cystic Fibrosis Registry. Summary Report 2011.© 2014; Institute of Public Health (WIV-ISP), Brussels, Belgium. 6. Cystic Fibrosis Trust.
UK Cystic Fibrosis Registry Annual Data Report 2014. © 2015; Cystic Fibrosis Trust; London, UK. 7. French Cystic Fibrosis. Registry Annual Report 2013. © Vaincre la
Mucoviscidose and Ined, 2015; Paris, France. 8. Mukoviszidose e.V. und Mukoviszidose Institut gemeinnützige Gesselschaft für Forschung und Therapienntwicklung
mbH. Beriichtsband Qualitätssicherung Mukoviszidose 2012. © 2013, Bonn, Germany. 9. Nederlandse Cystic Fibrosis Stichting. Dutch Cystic Fibrosis Patient Registry.
Report on the Year 2014. © 2015; NCFS: Baarn, Netherlands. 10. The Cystic Fibrosis Registry of Ireland. 2013 Annual Report. © CFRI, 2015; Dublin, Ireland.
11. Cystic Fibrosis Australia. Australian Cystic Fibrosis Data Registry 2013–16th Annual Report. © 2015; Cystic Fibrosis Australia; Baulkham Hills NSW, Australia.
12. Cystic Fibrosis Association of New Zealand. PORT CFNZ National Data Registry, 2014 Registry Report. Christchurch, New Zealand. 13. Bobadilla JL et al. Hum
Mutat. 2002;19(2):575-606. 14. Casals T et al. Hum Genet. 1993;91(1):66-70.
Country
% of Alleles
Tunisia13
9%
Spain13
8%
Greece
4%
13
Bulgaria13
4%
Austria
3%
Italy13
3%
13
•T
he G542X mutation was
found at a higher frequency
in certain regions of Spain,
including the Canary Islands
(25%), Murcia (21%),
Navarra (17%), and
Valencia (11%)14
4
The G542X mutation results in defective biosynthesis
of the CFTR protein1-3
Illustrative Example of Class I Defect
• G
542X is a nonsense
mutation, which produces
a premature stop codon1-3
CFTR Turnover
CFTR Function
A
T
A
U
G
C
G
C
CFTR Trafficking
CFTR gene
(DNA)
Golgi
complex
Endoplasmic
reticulum
Proteosome
A
G
C
T
A
A
U
mRNA strand
G
C
G
C
G
A
U
T
A
T
A
Rest of
CFTR
gene
CFTR Processing
A
T
T
C
Start
codon
Premature
stop codon
• T
he cell cannot synthesize
a full-length CFTR protein,
a Class I mutation1-2
• As
a result, few to no
CFTR proteins are present
at the apical cell surface1-2
Rest of
mRNA
strand
mRNA
Transcription
CFTR Synthesis
DNA
References: 1. Zielenski J. Respiration. 2000;67(2):117-133. 2. Welsh MJ, Smith AE. Cell. 1993;73(7):1251-1254. 3. Castellani C et al. J Cyst Fibros. 2008;7(3):179-196.
5
The G542X allele results in little to no total
CFTR activity1-4
Total CFTR activity can be defined as total ion transport mediated by
CFTR protein channels at the cell surface, depending on CFTR protein
quantity and function.4
CFTR
Quantity
G542X allele results
in few to no CFTR
channels at apical
surface
x
x
1
CFTR Function
Channel-open
Probability
Channel-open
Probability: N/A
x
x
2
Conductance
Conductance:
N/A
=
Total
CFTR Activity
=
Little to No
G542X-CFTR
Activity
3
1
A virtual absence of
G542X-CFTR protein
quantity…
2
…regardless of function
since few to no CFTR proteins
reach the surface…
3
…results in little to no
total CFTR activity
Defective
Synthesis
(Class I)
N/A, not applicable.
References: 1. Zielenski J. Respiration. 2000;67(2):117-133. 2. Welsh MJ, Smith AE. Cell. 1993;73(7):1251-1254. 3. Castellani C et al. J Cyst Fibros. 2008;7(3):179-196.
4. Sheppard DN et al. Nature. 1993;362(3):160-164.
6
Both CFTR alleles play a role in determining phenotype
or disease severity1-6
100%
No CF Disease
Normal individuals and CF carriers
CFTR-related Disorder
Total
CFTR
Activity
Clinical entities associated with CFTR
dysfunction that do not fulfill diagnostic
criteria for CF
Cystic Fibrosis
•A
G542X allele results
in little to no CFTR
activity. The phenotype
of a particular patient
is also influenced by
the mutation on the
other allele1-6
•G
542X typically results
in the indicated phenotypes
0%
Allele 1
Normal
Normal
Normal
Residual
Residual
Little
to None
Allele 2
Normal
Residual
Little
to None
Residual
Little
to None
Little
to None
Total CFTR Activity
Total CFTR Activity
Adapted from Zielenski J. Respiration.
2000;67(2):117-133.
References: 1. US CF Foundation, Johns Hopkins University, The Hospital for Sick Children. The Clinical and Functional TRanslation of CFTR (CFTR2).
http://www.cftr2.org. Accessed November 12, 2015. 2. deGracia J et al. Thorax. 2005;60(7):558-563. 3. Cystic Fibrosis Genotype-Phenotype Consortium. N Engl J Med.
1993;329(18):1308-1313. 4. Davis PB et al. Am J Respir Crit Care Med. 1996;154(5):1229-1256. 5. Castellani C et al. J Cyst Fibros. 2008;7(3):179-196. 6. Zielenski J.
Respiration. 2000;67(2):117-133.
7
G542X in combination with another allele that produces
little to no CFTR activity usually results in a CF phenotype1-5
CFTR Genotype
Modifier
Genes
Allele #1: G542X
Allele #2
Little to No
CFTR Protein
Activity
Little to No
CFTR Protein
Activity
Little to No
Total CFTR
Activity
CF Phenotype
In patients registered in the CFTR2
database with a G542X mutation on
1 allele and a pancreatic insufficient
mutation on the second allele1
Environmental
Factors
• E
levated sweat chloride
(average):103 mmol/L
• L
ung function decline
over time
• Pseudomonas colonization:
56% of patients
• Pancreatic insufficiency:
98% of patients
References: 1. US CF Foundation, Johns Hopkins University, The Hospital for Sick Children. The Clinical and Functional TRanslation of CFTR (CFTR2). http://www.cftr2.org. Accessed November 12, 2015. 2. deGracia J et al. Thorax.
2005;60(7):558-563. 3. Cystic Fibrosis Genotype-Phenotype Consortium. N Engl J Med. 1993;329(18):1308-1313. 4. Davis PB et al. Am J Respir Crit Care Med. 1996;154(5):1229-1256. 5. Castellani C et al. J Cyst Fibros. 2008;7(3):179-196.
8
Summary
•Loss of CFTR activity is the underlying cause of CF
•Levels of CFTR activity affect survival in CF
• G542X is the second most common CFTR mutation in the world
•The G542X mutation results in defective biosynthesis of the
CFTR protein
•The G542X allele results in little to no total CFTR activity
•Both CFTR alleles play a role in determining phenotype or
disease severity
•G542X in combination with another allele that produces
little to no CFTR activity usually results in a CF phenotype
9