GENETIC TESTINGVolume 9, Number 1, 2005© Mary Ann Liebert, Inc.

The 35delG Mutation in the Connexin 26 Gene (GJB2)Associated with Congenital Deafness: European Carrier

Frequencies and Evidence for Its Origin in Ancient Greece

GÉRARD LUCOTTE and FLORENT DIÉTERLEN

ABSTRACT

The 35delG mutation in the connexin 26 gene (GJB2) at the DFNB1 locus represents the most common mu-tation in Caucasian patients with genetic sensorineural deafness. This new meta-analysis concerns publishedcarrier frequencies of the 35delG mutation in 27 populations for 6,628 unrelated individuals in Europe andin the Middle East; the mean carrier frequency of the mutation is 1.9%. Compared on a regional basis, themost elevated carrier frequency value is of 1 individual carrier in 31 in southern Europe. It is probable thatthe 35delG mutation originated in ancient Greece and was subsequently propagated in other Mediterraneancountries (especially in Italy) during recent historical times.

20

INTRODUCTION

HEARING IMPAIRMENT is one of the most prevalent sensory dis-orders, affecting approximately 1/1,000 live births; of those

about one-half are believed to be genetic, bringing the number ofcongenital genetic hearing loss to 1/2,000. Autosomal recessivenonsyndromic hearing loss (ARNSHL) is the most common formof severe inherited sensorineural deafness (Van Camp et al., 1997)and accounts for about 80% of cases. It is an extremely hetero-geneous disorder with at least (Van Camp, 2003) a total of 67 ge-netic localizations: 30 autosomal recessive, 29 autosomal domi-nant, and 8 X-linked loci. A large proportion (up to 50%) offamilies with ARNSHL in Caucasian and European populationsare linked to DFNB1 on chromosome 13q (Gasparini et al., 1997);the gene involved in this type of deafness (GJB2) encodes the gapjunction protein connexin 26 (Kelsell et al., 1997).

In European, North American, and Mediterranean popula-tions, the most common recessive mutation in the CJB2 gene(Zelante et al., 1997) is a deletion of a single guanine nucleo-tide in a series of six guanines, known as 35delG (the mutationis a deletion resulting in a frameshift and termination of thecoded connexin 26 protein at amino acid 13). This mutationmay account for 70% of mutant alleles of GJB2, and the car-rier frequency of this mutation alone is estimated at around 1in 50 overall in Europe (Gasparini et al., 2000). However, someimportant differences exist among various populations, notablya lower carrier frequency in northern European countries com-pared with southern Europeans (Lucotte and Mercier, 2001).

Originally, the 35delG mutation was thought to be a deletionhot-spot, but more recent evidence (Van Laer et al., 2001) hassuggested that it may be due to a founder effect, i.e., an ancientmutation that has become widespread possibly because of someundefined heterozygote advantage.

In this study, we have compared carrier frequencies of the35delG mutation in various European and Middle Eastern pop-ulations, especially in populations of southern Europe.

METHODS

For each population observed, 35delG carrier frequency wascalculated as the number of heterozygous individuals reportedon n (number of subjects in each population studied). This car-rier frequency is approximately twice the 35delG allele fre-quency (� 2pq). Conformity with Hardy–Weinberg equi-librium (HWE) of genotypic frequencies was tested usinggenotypes observed and expected proportions, compared with2 � 2 contingency tables with 2 degrees of freedom (d.f.). Het-erogeneity between population samples was also evaluated bymeans of the �2 test, using a personal Instat software; for eachgroup, 35delG frequencies (q) were compared with mean al-lelic frequencies (qm) by the formula:

��� � ��qm �

n�pm��

Institute of Molecular Anthropology, 75005 Paris, France.

�q � qm�

and significance in allelic frequencies comparisons were ad-opted at the � � 5% level when ��� values were � 1.96.

The map of 35delG carrier frequencies was drawn with the“Spatial Analyst” program (Arcview software) using the classicalKringing procedure. We have used the inverse distance weighting(IDW) method, which is well adapted to scarce data (five neigh-bors in each quadrant, with a power of 2, so that influence is greaterat large distance); the grid has 250 rows and 355 columns.

RESULTS

35delG carrier and allele frequencies in 27 populations

Table 1 summarizes published carrier frequencies of the35delG mutation in various populations in Europe and in theMiddle East, with special emphasis on the new data corre-sponding to the studies published up to the end of 2003, sinceour own meta-analysis on the subject (Lucotte and Mercier,

2001). We excluded here the data regarding Estonia (Gaspariniet al., 2000), because the corresponding high 35delG frequencyreported represents an outliner value (Lucotte and Mercier,2001). This present meta-analysis concerns now a total of 6,628individuals, in 27 European and Middle Eastern populations.The mean carrier frequency of the 35delG mutation in these 27populations is 1.90%. All of the populations reported in Table1 are in apparent HWE for 35delG frequencies (�2 � 0 for eachpopulation). We found no homozygote in our samples, so theexpected homozygosity is at very low rate (p � 0.0001).

Heterogeneity between populations

To evaluate heterogeneity of 35delG values between the 27populations studied, we lumped together populations where theheterozygote numbers are �5 (Table 2). The test of hetero-geneity (d.f. � 15, because subjects were lumped into 16groups) we used to calculate the �2 value shows a significant�2 � 30.061 � 24.996, indicating heterogeneity among the 16groups compared. But there is no significant correlation be-

THE GJB2 MUTATION 35delG ASSOCIATED WITH CONGENITAL DEAFNESS 21

TABLE 1. 35delG MUTATION CARRIER FREQUENCIES IN 27 POPULATIONS IN EUROPE AND IN THE MIDDLE EASTa

% expectedCarrier carrier

Population Heterozygous frequencies frequenciesnumber Country Town/region individuals/nb and (range) values References

1 Finland Oulou 4/313 1.28 1.27 Löppönen et al. (2001)2 Norway Oslo 1/190 0.53 0.53 Gasparini et al. (2000)3 Denmark Glostrup 2/95 2.11 2.08 Gasparini et al. (2000)4 U.K. Manchester 0/119 0. 0. Gasparini et al. (2000)5 Germany Tubingen 6/376 1.60 1.58 Kupka et al. (2002)6 Poland Warsaw 3/150 2.00 1.98 Wiszniewski et al. (2001)7 The Netherlands Nijmegen 2/89 2.25 2.22 Gasparini et al. (2000)8 Belgium Antwerp 9/360 2.50 2.47 Storm et al. (1999)9 Czech republic Prague 4/195 2.05 2.03 Gasparini et al. (2000)

10 France Paris 14/512 2.73 2.70 Lucotte et al. (2001)(1.32–4.15)

11 Brittany 1/96 1.04 1.04 Gasparini et al. (2000)12 Corsica 11/328 3.35 3.30 Lucotte and Pinna (2003)13 Hungary Budapest 2/173 1.16 1.15 Bors et al. (2001)14 Austria Innsbruck 6/672 0.89 0.89 Löffer et al. (2001)15 Vienna 2/120 1.67 1.65 Frei et al. (2002)16 Slovenia Ljubliana 1/182 0.55 0.59 Gasparini et al. (2000)17 Italy Milan 6/150 4. 3.92 Estivill et al. (1998)

(2.–10.)18 Sardinia 4/116 3.45 3.39 Gasparini et al. (2000)

(2.–11.)19 Bulgaria Sophia 1/157 0.64 0.64 Gasparini et al. (2000)20 Spain Barcelona 3/130 2.31 2.28 Rabionet et al. (2000)21 Portugal Lisboa 4/179 2.23 2.21 Gasparini et al. (2000)22 Greece Athens 14/395 3.54 3.48 Antoniadi et al. (1999)

(1.72–5.37)23 Malta La Valletta 4/144 2.78 2.74 Gasparini et al. (2000)24 Turkey Istanbul 3/359 0.84 0.83 Uyguner et al. (2001)25 Ankara 12/674 1.78 0.18 Tekin et al. (2001)26 Lebanon Beirut 7/300 2.33 2.30 Mustapha et al. (2001)27 Jordan 0/54 0. 0. Medlej-Hashim et al. (2002)

Total 126/6628 1.90

aThe two-tailed test was used to calculate confidence intervals of % heterozygosity values, when it was possible.bn, Numbers of subjects in each population studied.

{

{{

{

tween the 35delG frequencies and longitude (r � �0.201; t �1.025 � 2.060, for d.f. � 25), or latitude (r � �0.215; t ��1.101), as previously described; so, the north-to-south in-creasing cline of 35delG frequencies found in our previousmeta-analysis (Lucotte and Mercier, 2001) disappears in thepresent study.

Table 3 summarizes the global value of 35delG carrier fre-quencies in three European broad regions (northern Europe,central Europe, and southern Europe) and in the Middle East.About one individual in 88 is a carrier individual of the muta-tion in central Europe, and one individual in 63 is a carrier bothin northern Europe and in the Middle East. In the various coun-tries of South Europe, the mean carrier frequency is of one in-dividual in 31.

A new European map of allele frequencies

A European 35delG allele map is represented on Fig. 1, onthe basis of carrier data compiled in Table 1. Four artificial dis-continuities in 35delG frequency values are introduced on themap. The regions of highest frequencies (�3.35%) correspondto Milan, Greece, Sardinia, and Corsica; regions of relativelyelevated frequencies (�2% �3.35%) correspond to Spain, Por-tugal, Paris, Belgium, the Netherlands, Denmark, Czech re-

public, Malta, and Lebanon; moderate values (�1% �2%) con-cern Finland, Germany, Hungary, Vienna, and Ankara, and lowvalues (below 1%) all the other countries.

DISCUSSION

The most characteristic result obtained for the 35delG fre-quencies in Europe concerns their relatively more elevated val-ues in the Mediterranean region: the carrier frequencies of35delG in the Mediterranean region (1/31) are higher than thecommon cystic fibrosis �F508 mutation (Lucotte et al., 1991,1995) and than the C282Y mutation of hemochromatosis (Lu-cotte and Mercier, 2000) in the same region.

35delG elevated frequencies result of an initialfounder effect

Because it has been argued (Denoyelle et al., 1997) that in35delG the deletion of one guanine from a stretch of six couldhave frequently arise through polymerase slippage (or the pres-ence of a chi consensus motif in the immediate vicinity), mostinvestigators have assumed that the high frequency of the mu-tation reflects the presence of a mutational hot spot within

LUCOTTE AND DIÉTERLEN22

TABLE 2. TEST FOR HETEROGENEITY OF 35delG VALUES BETWEEN THE 16 POPULATION GROUPS

HeterozygousPopulation groups individuals/na Expected carrier values �2

1 4/313 5.95 0.642–4 3/404 7.68 2.855 6/376 7.15 0.186,7,9 9/434 8.25 0.078 9/360 6.84 0.6810, 11 15/608 11.56 1.0212 11/328 6.24 3.6413, 15 4/293 5.57 0.4414 6/672 12.77 3.5916, 19 2/339 6.44 3.0717, 18 10/266 5.06 4.8320, 21, 23 11/453 8.61 0.6622 14/395 7.51 5.6124 3/359 6.82 2.1425 12/674 12.81 0.0526, 27 7/354 6.73 2.95

an, Number of individuals in each group.

TABLE 3. CARRIER FREQUENCIES OF THE 35delG REGIONS IN THE EUROPEAN

MUTATION IN BROAD GEOGRAPHIC REGIONS AND IN THE MIDDLE EAST

Heterozygous Approximateindividuals/na carrier

Broad geographic regions Population numbers and % heterozygosity frequency

Northern Europe 1–8, 10, 11, 14, 15 47/2942 � 1.60% 1/63Central Europe 9, 13, 16, 19 8/707 � 1.13% 1/88Southern Europe 12, 17, 18, 20–23 46/1442 � 3.19% 1/31Middle East 24–27 22/1387 � 1.59% 1/63

an, Total number of individuals tested in the four broad geographic regions.

GJB2. That several different haplotypes surround the 35delGmutation (Morell et al., 1998) has seemed another argument infavor of a mutational hot spot, but such a study has considereda very great interval (2 cM). Focusing on a region of less than70 kb and using six single-nucleotide polymorphisms (SNPs)mapped in the immediate vicinity of GJB2, the results obtainedin an other study (Van Laer et al., 2001) have established thatthe high frequency of 35delG was, in fact, the result of a foundereffect (rather than a mutational hot spot in GJB2), as one studypreviously suggested (Rabionet et al., 2000). The same study(Van Laer et al., 2001) also furnished an estimation of the ageof the mutation and a hypothesis about the geographic contextin which it originated and spread: the 35delG mutation was es-timated to be about 500 generations (approximately 10,000years) old. It is possible that this mutation originated some-where in the Middle East (Van Laer et al., 2001) and was spreadthroughout Europe along the two classic Neolithic populationmovement routes (the first route followed the coast of theMediterranean Sea, while the other followed the Danube andthe Rhine valleys to northern Europe).

A more recent study (Rothrock et al., 2003) indicated that35delG is a mutation derived from a common Caucasianfounder. Similarly, in Ashkenazi Jews, the most common causeof NSHL is the 167delT mutation of GJB2 (a deletion of a sin-gle T base); the conserved haplotype flanking 167delT suggeststhat this mutant allele is also a founder mutation (Morell et al.,1998), segregating in the Ashkenazi Jewish population. So thehigh frequencies of both the 35delG and 167delT in popula-tions have been shown to be the results of founder effects, ratherthan mutational hot spots.

Turkey is probably not the center of origin

The Anatolian origin of the 35delG mutation constitutes aninteresting hypothesis because of the relatively high frequency

of the mutation in the present population of Ankara (Tekin etal., 2001). It could be understood in the broad context of thegeneral diffusion model (Menozzi et al., 1978) postulating thatthe cline of gene frequencies from east to west in Europeanpopulations was carried out by Neolithic farmers. But 35delGcarrier frequencies are relatively low in the Middle East (Table3), and no carrier of that mutation was observed in a large re-cent series of 400 Palestinian controls (Shahim et al., 2002). InIsrael, the question was complicated by the fact that the otherconnexin 26 mutation (167delT) is the second most prevalentGJB2 mutation. Almost 40% of all deaf patients tested in Is-rael harbored GJB2 mutations, the majority of which corre-sponded to 35delG and 167delT mutations (Sobe et al., 2000);the modal haplotype carrying the 35delG mutation is the samein Palestinian and Israeli populations (Shahim et al., 2002).

Ancient Greece is possibly the center of origin of the35delG mutation

A general rule in population genetics is that the geographiccenter of a mutation corresponds to the area where it is the mostfrequent (Watterson and Guess, 1977). As shown in the twoprevious meta-analyses (Gasparini et al., 2000; Lucotte andMercier, 2001) and in the present one (Table 3), the highest fre-quencies of 35delG are found in southern Europe and in theMediterranean regions. A major drawback in this sort of studyis the fact that most studies used for the present meta-analysisare based on rather small population sets, to the point that spu-rious changes may significantly change the end result. Butamong the current data, Greece, with a heterozygosity � 3.54(Antoniadi et al., 1999), represents probably the focus. In thecurrent population of that country, the 35delG frequency hadsuch an elevated value (one-third of cases of prelingual non-syndromic deafness in Greek patients is caused by the 35delGmutation) that it was the first country in the world where a pro-

THE GJB2 MUTATION 35delG ASSOCIATED WITH CONGENITAL DEAFNESS 23

2000 2000

0–1

4000 Kilometers0

1–2

2–3

3–4

No Data

FIG. 1. European distribution of the 35delG carrier frequencies. The various nuances of greys correspond to artificial discon-tinuities, with density percentages as indicated in the text.

gram of prenatal diagnosis of deafness was started (Antoniadiet al., 2001).

Gene flow of the 35delG mutation from Greece to Italy, Sar-dinia, and Corsica, countries where the 35delG frequencies are�3.35%, could be explained by the Greek colonization of theso-called “Magna Graecia” in historical times (sixth centuryB.C.). A similar scheme is consistent with the results of a pre-vious general analysis (Piazza et al., 1988), showing a contin-uous gradient of several non-DNA genetic markers from Greeceto Southern Italy. Such an interpretation explains the relativelyhigh 35delG values in areas depicted in Fig. 1.

The underlying genetic mechanism accounting for the highprevalence of the 35delG mutation is unknown. Nance et al.(2000) have suggested that improved reproductive fitness com-bined with intermarriage among deaf people may have con-tributed to the high frequency of GJB2 deafness, and could rep-resent a novel mechanism for maintaining specific genotypesat unexpectedly high frequencies. That seems likely to be ap-plicable to some European, Mediterranean, and Oriental popu-lations where there has been a long tradition of intermarriagesamong the deaf. The high level of 35delG mutations in theMediterranean area suggests that heterozygote advantage for35delG exists, or existed, under certain circumstances. Giventhe widespread expression of the GJB2 gene in some tissues, arather reduced expression may confer a selective advantage viasome pathways (Meyer et al., 2002). If we hold it to be truethat changes in the mating structure and in the fitness of a deafpopulation has contributed to an increase in the frequency ofsome GJB2 mutation, this mechanism would be expected to in-crease the frequency of whichever allele is the most frequentin that population. Future studies may distinguish between theseand other mechanisms underlying the increased prevalence ofthe founder mutation 35delG of the GJB2 gene.

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Address reprint requests to:Pr. Gérard Lucotte

Center of Molecular Neurogenetics44, rue Monge

75005 Paris, France

E-mail: lucotte@hotmail.com

25THE GJB2 MUTATION 35delG ASSOCIATED WITH CONGENITAL DEAFNESS

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