American Journal of Medical Genetics 91:277–279 (2000)
CFTR Mutations in Three Latin
American Countries
C.M. Restrepo,1 L. Pineda,2 A. Rojas-Martı́nez,3 C.A. Gutiérrez,1 A. Morales,2 Y. Gómez,1
M.C. Villalobos,3 L. Borjas,2 W. Delgado,2 A. Myers,1 and H.A. Barrera-Saldaña3*
1
Unidad de Genética, Instituto de Ciencias Básicas, Facultad de Medicina, Universidad Colegio Mayor de Nuestra
Señora del Rosario, Bogotá, Colombia
2
Unidad de Genética Médica, Facultad de Medicina, Universidad del Zulia, Maracaibo, Zulia, Venezuela
3
Departamento de Bioquı́mica, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey,
Nuevo León, México
We analyzed 192 cystic fibrosis (CF) alleles
in three Latin American countries: Mexico,
Colombia, and Venezuela. Mutation screen-
ing was performed by polymerase chain re-
action (PCR) and a reverse dot blot detec-
tion kit that enables determination of 16 of
the most common CF mutations worldwide.
Mutations were detected in 47.9% of the
screened CF alleles. The most prevalent CF
allele was ⌬F508 (39.6%). The remaining 16
non-⌬F508 detectable mutations repre-
sented 8.3% of the CF alleles. Among them,
the G542X, N1303K, and 3849+10kb C>T
were the most common. Although the fre-
quency of ⌬F508 described here is lower
than that reported for Caucasian popula-
tions, including in Spain, it is remarkable
that mutation prevalences found in this
study resemble those observed in Spain.
Two of these mutations, G542X and
3849+10kb C>T, that were relevant in this
analysis, have a particularly high incidence
in Spanish communities. The low frequency
of ⌬F508 described here may be explained
by the Amerindian, Caucasian, and Black
admixture that occurred in Latin America
after the discovery of the New World, and
also by the probable occurrence of muta-
tions contributed by the original natives,
which were undetectable in this analysis.
Am. J. Med. Genet. 91:277–279, 2000.
© 2000 Wiley-Liss, Inc.
Grant sponsor: “Cátedras Patrimoniales de Excelencia II” from
the National Council for Science and Technology (CONACYT).
*Correspondence to: Dr. Hugo A. Barrera-Saldaña, Departa-
mento de Bioquı́mica, Facultad de Medicina, Universidad Au-
tónoma de Nuevo León. Av. Francisco I. Madero y Calle Dr. Edu-
ardo Aguirre Pequeño, Col. Mitras Centro, CP 64460. Monterrey,
Nuevo León, México. E-mail: hbarrera@uanl.mx
Received 7 June 1999; Accepted 4 January 2000
© 2000 Wiley-Liss, Inc.
KEY WORDS: cystic fibrosis; allele/muta-
tion frequencies; ethnic
groups; Latin America
INTRODUCTION
Cystic fibrosis (CF) is the most common autosomal
recessive disease in Caucasian populations [Boat et al.,
1989]. More than 800 mutations/polymorphisms have
been described since the positional cloning, identifica-
tion, and sequencing of the cystic fibrosis transmem-
brane regulator gene (CFTR) 10 years ago [CFGAC
web site]. The ⌬F508 mutation, a 3 basepair (3 bp)
deletion, results in the loss of the phenylalanine resi-
due at position 508 of the protein CFTR, and is the
most frequent CF-causing mutation [CFGAC, 1990].
This mutation accounts for approximately 70% of all
CF mutations and it is found particularly in Cauca-
sians [CFGAC, 1990]. The remaining 30% are com-
prised of more than 800 other mutations, generically
named non-⌬F508, affecting Caucasians and other
ethnic groups [CFGAC web site]. The ⌬F508 allele
frequencies show a northwest-southeast gradient
distribution across Europe ranging from 80–40%, re-
spectively [CFGAC, 1990; Romeo and Devoto, 1990].
Published data for CF mutations in Latin American
populations are scarce. They include some reports from
Argentina [CFGAC, 1990; Aulehla-Scholz et al., 1990],
Brazil [Raskin et al., 1999], Cuba [Collazo et al., 1995],
Mexico [Rojas-Martı́nez et al., 1992; Orozco et al., 1993;
Villalobos-Torres et al., 1997], some studies of Hispanic
patients in the USA [Grebe et al., 1994; Arzimanoglou
et al., 1995], and other isolated reports. The Latin
American populations are mixtures from immigrants
coming originally from Asia and the Pacific Islands
(Amerindians) and, more recently, from Europe and
Africa, after Columbus discovered America. Spaniards
brought the major Caucasian background present to-
day in the Spanish-speaking countries of Latin
America. It is possible that the recent immigrants may
have introduced new CF alleles, changing the allele
frequencies in the region. The present work determines
278 Restrepo et al.

the frequencies of 16 CFTR mutations in three Span- ranging from 47.8% in Mexico to 29.6% in Venezuela.
ish-speaking Latin American countries, and compares Detectable non-⌬F508 mutations accounted for 8.3% of
these frequencies with the CF allelic frequencies re- the CF alleles in the sample. These detectable non-
ported for Spain. ⌬F508 alleles were distributed as follows: 3.7% in Ven-
ezuela, 10.0% in Mexico, and 10.4% in Colombia. The
MATERIALS AND METHODS next three most common alleles determined in the pre-
sent study were G542X (4.7% present in the three
The present study analyzed 96 unrelated Latin countries studied), N1303K (1% present in Mexico and
American patients with CF diagnosis, distributed as Colombia), and 3849+10kb C>T (1% present only in
follows: 45 patients from Monterrey, Mexico (90 chro- two Mexican CF chromosomes). Besides ⌬F508 and
mosomes), 24 patients from Bogota, Colombia (48 chro- G542X, no other CF alleles were detected in the Ven-
mosomes), and 27 patients from Maracaibo, Venezuela ezuelan sample. In addition to these alleles, only three
(54 chromosomes). All patients were ascertained in ge- other CF mutations were detected: 621+1 G>T, S549N,
netic services in each city. The CF diagnosis was es- and W1282X. The G551D mutation, the third most
tablished by clinical findings of chronic pulmonary and/ common mutation worldwide, was not found in this
or gastrointestinal disease, with at least two abnormal analysis. Unknown mutations (undetectable with the
sweat chloride tests. Blood samples were drawn from kit used) represent 52.1% of the CF alleles in this
patients in whom clinical results were highly sugges- study. They ranged from 42.2–66.7% in the analyzed
tive of CF. countries.
Genomic DNA from whole blood was isolated from
leukocytes as previously described [Villalobos-Torres et DISCUSSION
al., 1997]. The isolated DNA from each patient was
amplified by polymerase chain reaction (PCR) using a The distribution of CF mutations reported here fol-
kit for reverse dot blot detection of 16 common CF mu- lows the trend of Caucasian populations, in which the
tations: ⌬F508, R553X, G542X, G551D, N1303K, ⌬F508 frequency is overrepresented and the other mul-
W1282X, R117H, R334W, R347P, A455E, ⌬I507, tiple CF mutations account only for very small percent-
1717-1 G>A, R560T, 3849+10kb C>T, 621+1 G>T, ages. But the average frequency of ⌬F508 mutation in
S549N [Villalobos-Torres et al., 1997]. This kit in- the studied countries is lower than the frequency es-
cluded the respective pairs of primers to analyze the tablished for North America and Europe (about 66%)
different mutated segments along the CF gene. The [CFGAC, 1994]. Differences in the prevalence of ⌬F508
biotin-labeled amplicons were denatured and hybrid- among the analyzed countries are notorious. The
ized with immobilized allele-specific oligonucleotides prevalence found in Mexico is very close to those fre-
probes (ASOs) as described previously [Villalobos- quencies of about 50% reported in Spain, the USA, and
Torres et al., 1997]. Brazil (Table II) [Casals et al., 1997; Grebe et al., 1994;
Arzimanoglou et al., 1995; Raskin et al., 1999]. Preva-
RESULTS lences of ⌬F508 found in Colombia and Venezuela are
close to those of 39% and 34% found in a previous Mexi-
The present study characterized the molecular defect can study and in Cuba, respectively [Orozco et al.,
in 192 CF alleles from Colombia, Mexico, and Venezu- 1993; Collazo et al., 1995].
ela using a panel for ascertainment of the 16 most com- G542X mutation, the second most common allele
mon CFTR mutations worldwide. Results of this study worldwide, has a higher prevalence in Colombia (6.3%).
are shown in Table I. The overall diagnostic efficacy of In Mexico, the prevalence found is about half that of
the PCR-ASO probe approach for the detection of CF 8.4% found in Spain [Casals et al., 1997], but a previ-
mutations in the analyzed patients was 47.9% (33.3, ous study of this mutation in Mexican CF patients re-
45.8, and 57.8% for Venezuela, Colombia, and Mexico, vealed a frequency of 7.2% [Villarreal et al., 1996].
respectively). The most common mutation was the N1303K and 3849+10kb C>T alleles, the third and
⌬F508 deletion, with an overall frequency of 39.6%, twelfth most common CF mutations in the world [CF-
GAC, 1994], represent the third most common alleles
TABLE I. Frequencies and (Chromosome Number) of CF
in our study. The three additional mutations found
Mutations Detected in Three Latin American Countries (W1282X, 621+1G>T, and S549N) represent only 1.5%
of the CF allele occurrence in this analysis.
Mexico Colombia Venezuela Total This study suggests an important Spanish contribu-
CF mutation % (90) % (48) % (54) % (192)
tion for the 47.8% of CF mutations ascertained in these
⌬F508 47.8 (43) 35.4 (17) 29.6 (16) 39.6 (76) three countries, but it also demonstrates regional dif-
G542X 4.4 (4) 6.3 (3) 3.7 (2) 4.7 (9) ferences in allele prevalence. Besides the differences in
N1303K 1.1 (1) 2.1 (1) 0.0 (0) 1.0 (2)
3849 + 10kb
⌬F508 occurrence, the allele frequencies of G542X and
C>T 2.2 (2) 0.0 (0) 0.0 (0) 1.0 (2) N1303K mutations are similar for Mexico and Colom-
W1282X 0.0 (0) 2.1 (1) 0.0 (0) 0.5 (1) bia, but differ from those found in Venezuela. These
621 + 1 G > T 1.1 (1) 0.0 (0) 0.0 (0) 0.5 (1) differences in ethnic background have been outlined
S549N 1.1 (1) 0.0 (0) 0.0 (0) 0.5 (1) before in studies in the USA when countries of origin of
Non-⌬F508a 10.0 (9) 10.4 (5) 3.7 (2) 8.3 (16) CF chromosomes were analyzed for the southwestern
Unknown 42.2 (38) 54.2 (26) 66.7 (36) 52.1 (100)
and eastern US-Latin patients [Grebe et al., 1994;
a
Detected with the 16 CF mutation panel in this study. Arzimanoglou et al., 1995]. Here, we suggest a more
 CF Mutations in Latin America 279

TABLE II. Percentage of CF Mutations Detected in Studies of Latin American Populations*

Brazil US Latins US Latins Spain Worldwide
[Raskin et al., [Grebe et al., [Arzimanoglou [Casals et al., [CFGAC,
This report 1999] 1994] et al., 1995] 1997] 1994]
CF mutation High prevalence (n ⳱ 192) (n ⳱ 172) (n ⳱ 129) (n ⳱ 48) (n ⳱ 1280) (n ⳱ 43,849)
⌬F508 Caucasian 39.6 47.0 45.7 47.9 53.2 66.0
G542X Spain 4.7 5.5 5.4 2.1 8.4 2.4
G551D England 0.0 0.2 0.0 2.1 0.3 1.6
N1303K Italy 1.0 2.3 0.0 6.3 2.7 1.3
W1282X Jew. Ashkenazi 0.5 na 0.8 0.0 0.8 1.2
R553X Germany 0.0 0.8 0.8 2.1 0.3 0.7
621 + 1 G > T French-Canadian 0.5 na 0.0 0.0 0.5 0.7
R1162X Italy na na 1.6 0.0 1.6 0.3
3849 + 10kb C > T J. Sephardic/Spain 1.0 na 2.3 0.0 0.4 0.2
R334W Not determined 0.0 na 1.6 6.3 1.6 0.1
S549N Not determined 0.5 na 0.0 na na <0.1
*na, not ascertained.

complicated picture, resulting from subregional differ- REFERENCES

ences in ethnic background that are common inside the
three studied countries. Although there are no confi-
dent demographic studies to make these determina-
tions, Monterrey, Mexico, is a city with a predomi-
nantly Spanish-Native background (Mestizo), perhaps
similar to the background prevalent in Bogota, Colom-
bia. Maracaibo, Venezuela, has a different background,
due to an important Black contribution (Mulatto and
Zambo). A recent published report from Brazil also re-
marks these subregional differences [Raskin et al.,
1999].
The detection efficacy of the ASO panel used (47.9%)
was low. Studies of Latin American patients carried
out in the USA determined 58% and 67% of CF alleles
[Grebe et al., 1994; Arzimanoglou et al., 1995]. The
study performed in Brazil detected 56% of CF alleles
with a 5-CF mutation panel [Raskin et al., 1999]. The
high frequency of undetectable CF mutations (52.1%)
in the present study requires additional analyses to
determine their nature and their contribution to the
genetic pool in each country or subregion. The efficacy
of the CF-ASO probe methodology used may be in-
creased if African mutations, as 3120+1 G>A are in-
cluded. This will be of particular relevance for Colom-
bia and Venezuela, which have an important Black
influence. Additionally, it can be expected that some
“CF Amerindian alleles” will be found that currently
remain undiscovered, which will be important to de-
sign new ASO panels for the ascertainment of CF mu-
tations and to develop genetic counseling in Latin
America.
ACKNOWLEDGMENTS
Arzimanoglou I, Tuchman A, Li Z, Gilbert F. 1995. Cystic fibrosis carrier
screening in Hispanics. Am J Hum Genet 56:544–547.
Aulehla-Scholz C, Kaiser R, Weber J, Pivetta O, Eigel A, Dworniczak B,
Olek K, Horst J. 1990. The frequency of the CF ⌬F508 deletion in CF
chromosomes of different ethnic origin. Hum Genet 85:392–393.
Boat TF, Welsh MJ, Beaudet AL. 1989. Cystic fibrosis. In: Scriver CR,
Beaudet AL, Sly WS, Valle D, editors. The metabolic basis of inherited
disease. New York: McGraw-Hill. p 2649–2680.
Casals T, Ramos MD, Gimenez J, Larriba S, Nuñes V, Estivill X. 1997.
High heterogeneity for cystic fibrosis in Spanish families: 75 mutations
account for 90% of chromosomes. Hum Genet 101:365–370.
CFGAC (Cystic Fibrosis Genetic Analysis Consortium). 1990. Worldwide
survey of the ⌬F508 mutation-report from the Cystic Fibrosis Genetic
Analysis Consortium. Am J Hum Genet 47:354–359.
CFGAC (Cystic Fibrosis Genetic Analysis Consortium). 1994. Population
variation of common cystic fibrosis mutations. Hum Mutat 4:167–177.
CFGAC (Cystic Fibrosis Genetic Analysis Consortium) Web Site. Cystic
Fibrosis Mutation Data Base. http://www.genet.sickkids.on.ca/cftr/
Collazo T, Magarino C, Chavez R, Suardiaz B, Gispert S, Gomez M, Rojo M,
Heredero L. 1995. Frequency of delta-F508 mutation and XV2C/KM19
haplotypes in Cuban cystic fibrosis families. Hum Hered 45:55–57.
Grebe TA, Seltzer WK, De Marchi J, Silva DK, Doane WW, Gozal D, Rich-
ter SF, Bowman MC, Norman RA, Rhodes SN, Hernried LS, Murphy S,
Harwood I, Accurso FJ, Jain KD. 1994. Genetic analysis of Hispanic
individuals with cystic fibrosis. Am J Hum Genet 54:443–446.
Orozco L, Salcedo M, Lezana JL, Chavez M, Valdez H, Moreno M, Carnev-
ale A. 1993. Frequency of ⌬F508 mutation in a Mexican sample of
cystic fibrosis patients. J Med Genet 30:501–502.
Raskin S, Phillips JA, Kaplan G, McClur M, Vnencak-Jones C, Rozov T,
Gardieri JM, Marostica P, Abreu F, Giugliani R, Reis F, Rosario NA,
Ludwig N, Pereira L, Faucz F, Gabardo J, Culpi L. 1999. Geographic
heterogeneity of 4 common worldwide cystic fibrosis non-⌬F508 muta-
tions in Brazil. Hum Biol 71:111–121.

We thank Dr. Randall Saiki from Roche Molecular
Systems for providing the 16 CFTR mutation detection
kits, Dr. Fernando Rivas and Dr. José Marı́a Cantú at
the División de Genética, CIBO, IMSS in Guadalajara,
Mexico, for valuable suggestions, and R.M. Chandler-
Burns for critical reading of the manuscript. A.R.-M. is
supported by the “Cátedras Patrimoniales de Exce-
lencia II” program from the National Council for
Science and Technology (CONACYT). H.A.B.-S. thanks
CONACYT and the Global Network for Cell and Mo-
lecular Biology (GNMCB) for their support.
Rojas-Martinez A, Vazquez-Aleman RM, Gustincich S, Cantú JM, Barrera-
Saldaña HA. 1992. El alelo ⌬F508 en familias mexicanas. Bol Med
Hosp Infant Mex 49:335–341.
Romeo G, Devoto M. 1990. Population analysis of the major mutation in
cystic fibrosis. Hum Genet 85:391–391.
Villalobos-Torres C, Rojas-Martinez A, Villarreal-Castellanos E, Cantú
JM, Sanchez-Anzaldo FJ, Saiki RK, Barrera-Saldaña HA. 1997. Analy-
sis of 16 cystic fibrosis mutations in Mexican patients. Am J Med Genet
69:380–382.
Villarreal MT, Chavez M, Lezana JL, Cuevas F, Carnevale A, Cordova E,
del Angel RM, Orozco L. 1996. G542X mutation in Mexican cystic fi-
brosis patients. Clin Genet 49:54–56.