X-linked recessive inheritance
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FRAXA syndrome

Fragile X Syndrome is the most common inherited cause of mental retardation, and is associated with autism. more...

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Causes

The fragile X syndrome is a genetic disorder caused by mutation of the FMR1 gene on the X chromosome. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 4000 females.

Normally, the FMR1 gene contains between 6 and 53 repeats of the CGG codon (trinucleotide repeats). In people with the fragile X syndrome, the FMR1 allele has over 230 repeats of this codon.

Expansion of the CGG repeating codon to such a degree results in a methylation of that portion of the DNA, effectively silencing the expression of the FMR1 protein.

This methylation of the FMR1 locus in chromosome band Xq27.3 is believed to result in constriction and fragility of the X chromosome at that point, a phenomenon that gave the syndrome its name.

The mutation and methylation of the FMR1 gene lead to the transcriptional silencing of the fragile X-mental retardation protein, FMRP. In normal individuals, FMRP binds and facilitates the translation of a number of essential neuronal RNAs. In fragile X patients, however, these RNAs are not translated into proteins. The various sequelae of fragile X syndrome result.

Transmission of the Fragile X

The diagram (above) of X-linked recessive inheritance is not entirely inappropriate but it markedly oversimplifies the situation and does not provide a sufficient foundation for genetic counseling with the fragile X syndrome.

Because males normally have only one copy of the X chromosome, those males with significant trinucleotide expansion at the FMR1 locus are symptomatic. They are mentally retarded and may show various physical features of the fragile X syndrome.

Females have two X chromosomes and thus have double the chance of having a working FMR1 allele. Females carrying one X chromosome with an expanded FMR1 gene can have some signs and symptoms of the disorder or be normal.

Males with the fragile X cannot transmit it to any of their sons (since males contribute a Y chromosome, not an X, to their male offspring.)

Females carrying one copy of the fragile X can transmit it to their sons or daughters. Sons who receive the fragile X are at high risk for mental retardation. Daughters who receive the fragile X may appear normal or they may be mentally retarded, usually to a lesser degree than boys with the syndrome.

Symptoms

Aside from mental retardation, prominent characteristics of the syndrome include an elongated face, large or protruding ears, large testicles (macroorchidism), and low muscle tone. Behavioral characteristics may include stereotypic movements (e.g., hand-flapping) and atypical social development, particularly shyness and limited eye contact. Some individuals with the fragile X syndrome also meet the diagnostic criteria for autism.

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Stability of the FMR1 CGG repeat in a Basque sample
From Human Biology, 2/1/99 by Arrieta, I

Abstract The fragile X syndrome is an X-chromosome-linked dominant disorder with reduced penetrance. It is the most common inherited form of mental retardation. The molecular basis is usually the unstable expansion of a CGG trinucleotide repeat in the 5' untranslated region of the first exon of the FMRI gene, which resides at chromosome position Xq27.3 and is coincident with the cytogenetic fragile site FRAXA, which characterizes the syndrome. In the Biscay province of the Basque Country the prevalence of FRAXA in a mentally retarded sample of nonBasque origin is in the range of other analyzed Spanish populations. In the sample of Basque origin we have not found FRAXA site expression and the repeat size is in the normal range. Based on this, we have examined FMRI gene stability in normal individuals of Basque origin from the Biscay province. This study is based on a sample of 242 X chromosomes. The results from the CGG repeat region of FMRI indicate that a prevalence of predisposing normal alleles toward repeat instability in the Basque population is 0.00% or near to it. This could be I of the explanations of the apparently low fragile X syndrome incidence found in the Basque mentally retarded sample analyzed by us. This low incidence does not seem to be associated with the flanking microsatellite markers.

Since the early 1900s an excess of males has been noted among mentally retarded persons. Studies of many family pedigrees suggest that a sex-linked mode of transmission is involved in certain cases of mental retardation.

In 1969 the fragile X site, located on the long arm of the X chromosome in the subband Xq27.3 (FRAXA), was described (Lubs 1969). Several years after its recognition, the fragile X site was determined to be associated with X-chromosome-linked mental retardation in several families and was believed to be responsible for the condition that had been called Martin-Bell syndrome (Martin and Bell 1943). The latter name is now a synonym for fragile X syndrome. The fragile X syndrome is an X-chromosome-linked dominant disorder with reduced penetrance (Nelson 1995). It is the most commonly inherited form of mental retardation (Brown and Jenkins 1992). The estimated prevalence in whites of European origin has recently been lowered to approximately 1 in 4000 males (Turner et al. 1996). The molecular basis of fragile X syndrome is usually the unstable expansion of a CGG trinucleotide repeat in the 5' untranslated region of the first exon of the FMR1 gene, which resides at map position Xq27.3, coincident with the cytogenetic fragile site (FRAXA) that characterizes the syndrome (Kremer et al. 1991; Oberle et al. 1991; Verkerk et al. 1991; Yu et al. 1991).

The CGG repeat number is polymorphic in the normal population and varies in size from 6 to 52 repeats. These alleles are usually stable during transmission (Fu et al. 1991; Arinami et al. 1993; Brown et al. 1993; Snow et al. 1993; Eichler et al. 1994; Hirst et al. 1994; Zhong et al. 1994; Kunst et al. 1996). Penetrant fragile X syndrome patients exhibit repeat lengths greater than 230 triplets, often approaching 1000 repeats (Kremer et al. 1991).

Recent studies have strongly implicated not only the overall repeat length as possibly contributing toward expansion but, more important, the purity of CGG repeat (or lack of interrupting AGG triplets) as playing a major role (Eichler et al. 1994; Kunst and Warren 1994).

Kunst et al. (1996) reported that the concept of predisposing normal alleles is supported by studies that have demonstrated linkage disequilibrium for polymorphisms near the FMR1 repeat. Brown et al. (1996) also demonstrated that the FMRI triplet repeat and 2 nearby microsatellites (FRAXAC1, located at 7 kb, and DXS548, located at 150 kb) show positive allele size association. The larger alleles tend to occur together, and the smaller alleles also tend to occur together. Also, fragile X chromosomes are more frequently found on the larger combined microsatellite-allele haplotypes.

Cases of fragile X syndrome have been observed among diverse human populations, suggesting that there is no particular ethnic predilection to the development of the disease (Howard-Peebles and Stoddard 1980; Rivera et al. 1981; Venter et al. 1981; Soysa et al. 1982; Rhoads 1984; Eichler and Nelson 1996).

A cytogenetic and molecular study undertaken in our laboratory (unpublished data) on a mentally retarded sample (with unknown cause of retardation), obtained from institutions for mentally retarded persons from the Biscay province of the Basque Country [including an autistic sample previously analyzed by Arrieta et al. (1990, 1996)], has shown that the frequency of the FRAXA full mutation in the population of non-Basque origin (10.20%) is in the range of other Spanish populations analyzed: 6.4% (Martinez 1994) to 12% (Gabarron et al. 1992). In the sample of Basque origin we have not found the FRAXA site expression, and the repeat size is in the normal range.

A review by Hashimoto et al. (1993) described mentally retarded populations with a fragile X frequency near or even 0.00%. Recent studies in other trinucleotide repeat loci (Ashley and Warren 1995) also suggest that there are significant differences among various populations in the repeat length alleles and haplotype backgrounds. As Kunst et al. (1996) suggested, "normal allelic frequencies may vary among populations and in some instances have an impact on the relevant disease incidence in that population" (p. 514). They discussed the absence of normal alleles predisposed to expansion in some populations.

Taking these data together, we examine FMRI gene stability in the normal population of Basque origin from Biscay province to see whether the results obtained in the mentally retarded population of Basque origin could be related to a low incidence of predisposing normal alleles for repeat instability.

Materials and Methods

DNA Sample. This study is based on a sample of 242 X chromosomes. This sample is made up of 170 unrelated normal individuals of Basque origin (98 males, 72 females). The Basque Country comprises 3 provinces in Spain (Biscay, Alava, Guipuzcoa). In this study the sample is from the Spanish Basque province of Biscay. The sample was chosen on the basis of 2 criteria: (1) the 8 surnames and (2) the grandparents' and great grandparents' places of birth (all should have been born in Biscay). Surnames in the Basque population are a good identifier of origin because they are different not only from other Spanish regions but also from region to region within the Basque Country. With these selection criteria, we can go back at least 3 generations into the pre-industrial period, when there was little migration.

FMR1 CGG Repeat Distribution and AGG Interspersion. To test whether a possible lack of longer alleles might explain the low incidence of fragile X syndrome in Basques, we carried out a study of the allele distribution of the CGG repeat of the FMRI gene in a normal sample from the Basque Country.

Recent studies have strongly implicated not only the overall repeat length as possibly contributing toward expansion but, more important, the purity of the CGG repeat (or lack of interrupting AGG triplets) (Eichler et al. 1994; Kunst and Warren 1994). Accordingly, we also tested the purity of CGG repeats in this population.

The copy number of the CGG repeat was determined by measuring the length of products of the polymerase chain reaction (PCR). PCR amplifications of FMRI CGG repeats were carried out according to the method of Brown et al. (1993) with minor modifications and using the primers recommended by Fu et al. (1991). Women who showed only 1 band by PCR amplification and who were apparently homozygous were also examined by Southern blot hybridization of genomic DNAs digested with PstI with the probe Px6, kindly provided by D.L. Nelson, and according to the method of Yu et al. (1992). The verification of the obtained sizes was made by comparison to samples that had already been estimated and had been sent to us by F. Prieto (La Fe Hospital, Valencia, Spain).

Analysis of AGG interruptions within the CGG repeat was also carried out using PCR amplification and MnlI restriction analysis (Eichler et al. 1994; Zhong et al. 1995).

FRAXAC1 and DXS548 Repeat Distribution and Haplotype Analysis. We tested our sample with the flanking microsatellite markers FRAXAC1 and DXS548 to verify whether the alleles that are frequently found on European and Caucasian FMRI founder chromosomes are present in Basques. We have also studied the allele size association between (CGG)n and these flanking markers.

The CA repeats FRAXAC1 (Richards et al. 1991) and DXS548 (Riggins et al. 1992) were studied by PCR with oligonucleotide primers described by Zhong et al. (1994) for FRAXAC1 and by Martinez (1994) for DXS548.

The sizes of the PCR products were verified for DXS548 by comparison to samples that had already been estimated and that had been supplied by F. Prieto (La Fe Hospital, Valencia, Spain) and for FRAXAC1 by comparison to samples supplied by M.C. Hirst (Oxford University, Oxford, England) and P.A. Jacobs (Salisbury Hospital, Salisbury, England).

Statistical Analysis. Statistical methods used in the analysis of the data are the following: To assess the polymorphism of the loci, we calculated Nei's (1978) unbiased estimate of expected heterozygosity. To test whether the observed genotype distribution conforms to Hardy-Weinberg expectations, we carried out an exact test of homogeneity using the method proposed by Odelberg (1989). Last, to examine the allele size association among the loci, we used Pearson's correlation coefficient and the Fisher exact test (Zar 1996).

Results

FMR1 CGG Repeat Distribution and AGG Interspersion. Among 242 X chromosomes there were 21 different CGG repeat length alleles. As shown in Figure 1, the CGG alleles range from 19 to 43 repeats. The most common allele was 30 repeats (46.28%). Two minor peaks are present at 20 repeats (8.26%) and 23 repeats (10.33%). Only 11.41% of the sample has alleles over 31 repeats and only 2.65% has over 37 repeats. Of the females tested 22.22% were homozygous. The most common CGG genotypes were 30/30 (15.42%) in homozygous females and 20/30 (5.50%) in heterozygous females. We did not observe any difference in the distribution of CGG repeats between males and females.

The genotypes of 72 unrelated females were consistent with those expected from allele frequencies. Observed frequencies of homozygotes and heterozygotes did not deviate significantly from the expected values under Hardy-Weinberg equilibrium (chi^sup 2^ = 0.21, p = 0.66).

The results of the analysis of AGG interruptions within the FMRI CGG repeats show that chromosomes lacking AGG interruptions were not observed. The maximum number of AGG interruptions is 3, and these interruptions were found in chromosomes with allele sizes of 36 and 39. Only the smallest alleles (

As for other analyzed populations, a periodicity of 9 or 10 repeats between AGG interruptions has been identified (Eichler et al. 1995). According to what has been obtained for the largest alleles (41 and 43 repeats), the largest tract of pure CGG repeats is 23 repeats.

FRAXAC1 and DXS548 Repeat Distribution and Haplotype Analysis. Figure 2 shows the distributions of FRAXAC1 and DXS548 alleles. There are 5 different alleles for both loci. The range includes alleles 17 to 21 for FRAXAC1 and 194 to 208 for DXS548. The most frequent was 19 for FRAXAC1 (76.44%), and 194 for DXS548 (68.59%). Of the 72 females tested 61.11% and 54.16% were homozygous for FRAXAC1 and DXS548, respectively. The most common genotypes were 19/19 (58.35%) for FRAXAC1 and 194/194 (33.87%) for DXS548 in homozygous females. The most common genotypes were 18/19 (19.44%) for FRAXAC1 and 194/196 (17.55%) for DXS548 in heterozygous females. The observed frequencies of heterozygotes and homozygotes (chi^sup 2^ = 0.003, p = 0.92, for FRAXAC1; chi^sup 2^ = 0.28, p = 0.62, for DXS548) did not deviate from the expected number based on the allele frequencies. Therefore the examined population does not deviate from Hardy-Weinberg equilibrium at these loci. The unbiased expected heterozygosity was 39.49% for FRAXAC1 and 48.96% for DXS548.

Analysis of both microsatellites together showed that there were 13 haplotypes. The most common were 194/19 (61.22%) and 196/19 (14.28%).

Allele Association between FMRI CGG and Microsatellite Markers. To describe numerically the allele size association between FRAXAC1, DXS548, and FMR] CGG repeats, we calculated the correlation coefficients for the repeat lengths (Table 1). As in the studies of Zhong et al. (1995) and Brown et al. (1996), these repeats showed significantly positive correlations with each other.

In general, for both microsatellites the largest alleles were associated with the largest CGG repeats. Typing for FRAXAC1 (Table 2) showed that among alleles with less than 31 repeats, only 7.06% had the largest alleles 20 and 21, whereas among alleles with greater than 31 repeats 46.13% had these alleles. The results of Fisher's exact test demonstrate a significant linkage disequilibrium between CGG repeats and the 18 and 21 alleles (p

Typing for DXS548 (Table 3) showed that among alleles with less than 31 repeats, only 3.53% had the largest alleles 204-208, and among alleles with greater than 31 repeats 38.46% had the largest alleles. The results of Fisher's exact test show a significant linkage disequilibrium between CGG repeats and the 194, 202, and 204 alleles (p

As is apparent from Table 4, typing the combined FRAXAC1/DXS548 haplotypes also showed that the largest microsatellite allele size was much more commonly associated with the largest CGG repeat sizes. Overall, 69.41% of the sample with less than 31 repeats has the most common haplotype 194/19, but only 7.69% of the sample with greater than 31 repeats has this haplotype. The results of Fisher's exact test show that the association of the 194/19 haplotype with less than 31 repeats and the association of the 196/ 18, 202/18, 202/21, and 204/21 haplotypes with greater than 31 repeats are significant (p

Furthermore, the calculated heterozygosities for the FRAC1, DX.and the combined haplotypes were increased among the largest FMR1 allele sizes, as indicated in Table 5.

Discussion

In the 20th century the Basque province of Biscay has undergone industrialization that has been the starting point for a great evolution of the population. Since 1900, the population has quadrupled. This strong increase in the population is due in large measure to the arrival of people from Spanish non-Basque regions. As a consequence, the present population of Biscay province is made up to a large extent of 2 recently admixed descendants (Basque and non-Basque origin). There is another group of people of nonBasque origin, and there is a percentage of people with only Basque origin. Our previous research has shown that the frequency of the fragile X mutation in the non-Basque Biscay population is in the range of other Spanish nonBasque populations. However, in the sample with Basque origin the site causing FRAXA expression has not been found and the size of the repeat is in the normal range. According to McKeigue (1997), when migrant groups living in the same environment have different disease rates that are not accounted for by adjusting for known environmental determinants of disease risk, genetic explanations should be considered.

To test a possible genetic explanation for the low incidence of fragile X syndrome in the Basque population, we carried out a study of FMR1 gene stability in the normal population from Biscay province. Because not only the length but also the purity of CGG repeats seem to be important factors to stabilize trinucleotide repeats, these were the first aspect we analyzed.

The most outstanding result of FMRI CGG repeat analysis is that the allele with the largest size in the Basque population is smaller than the largest alleles of other European and Caucasian populations (Martinez 1994; Chiurazzi, Genuardi et al. 1996; Chiurazzi, MacPherson et al. 1996; Syrrow et al. 1996; Zhong et al. 1996; Brown et al. 1993), although the same mode is observed in most other populations. The frequency of the "gray zone" alleles is also lower. According to Fu et al. (1991), Heitz et al. (1992), Yu et al. (1992), and Rousseau et al. (1995), the probability of expansion to a full mutation increases with the size of a premutation; besides, "gray zone" alleles may be unstable (Sherman 1995). Therefore, if FMR1 gene stability depended only on the CGG repeat size, we would think that in the Basque population the incidence of predisposing alleles would be small, because there are no alleles in the premutation range and few alleles in the gray zone. A previous study carried out by our research group (Arrieta et al. 1997) on spinal and bulbar dystrophy or the Kennedy illness gene (SBMA) revealed that in the healthy Basque population the range of the allele size variation is enlarged in the lowest values and reduced in the highest ones; this also suggests that the incidence of the illness could be low in this population.

The heterozygosity of FMRI is 88% in Finland and 83% in Italy. The heterozygosity of this locus is slightly less in Basques. According to Eichler and Nelson (1996), this is expected because the population under investigation here has been subjected to geographic and cultural isolation.

Another factor that can predispose the FMRI gene to instability is the presence of a long CGG repeat sequence without AGG interruptions (Eichler et al. 1994; Hirst et al. 1994; Kunst and Warren 1994; Snow et al. 1994; Zhong et al. 1996). A comparison of stable and unstable alleles of similar size in the general population revealed that all unstable alleles had lost 1 or both of their AGG interruptions. In the Basque population we have not found alleles without AGG interruptions. Besides, the frequency of alleles that carry 2 AGG interruptions is not lower in "gray zone" alleles (>35 repeats) than in alleles with less than 35 repeats.

Morton and MacPherson (1992) proposed the existence of a class of normal FMR1 alleles, called S, that are predisposed to transition to premutation, or Z alleles, which form the ancestral pool from which fragile X chromosomes are derived. Kunst and Warren (1994) proposed that the S alleles are those normal alleles with greater than 24 perfect CGG repeat tracts. Morton and MacPherson (1992) estimated that at equilibrium the frequency of S alleles was between 0.5% and 4%. According to Kunst and Warren (1994), 2% of normal X chromosomes have greater than 24 perfect CGG repeats, and besides, these perfect CGG repeat tracts were observed among the largest (34-52) repeats. Accordingly, the incidence of the normal predisposing alleles in the Basque Biscayan population should be 0.00% or close to 0.00%. This frequency would be in the lower range proposed by Morton and MacPherson (1992). If this is so, we can deduce that, in relation to the AGG interspersion, the alleles of the population that we have analyzed show stability.

There has been some uncertainty whether FMRI alleles containing a single AGG interruption or lacking interruptions altogether result from the loss of AGG triplets from a progenitor allele containing 2 interruptions or arise from independent founder alleles. The data obtained by Kunst et al. (1996) suggest that FMR1 alleles with a single AGG interruption or no AGG interruptions can arise from CGG repeats containing 2 AGG triplets. The suggestion of Kunst et al. (1996) is also used for supporting the earlier ideas of Eichler et al. (1994) and Kunst and Warren (1994). The data obtained in our population do not contradict this suggestion, and they could indicate that the alleles found in the Basque Biscayan population come from founder alleles that have kept the presence of AGG interruptions through generations.

The analysis of FRAXAC1 and DXS548 repeat distributions shows that the most frequent alleles coincide with those found in other European and Caucasian populations (Richards et al. 1992; Buyle et al. 1993; Hirst et al. 1993; Jacobs et al. 1993; Oudet, von Koskull et al. 1993; Haataja et al. 1994; MacPherson et al. 1994; Malmgren et al. 1994; Zhong et al. 1994, 1995, 1996; Chiurazzi, Genuardi et al. 1996; Chiurazzi, MacPherson et al. 1996; Syrrow et al. 1996). FRAXAC1 heterozygosity is slightly lower compared with heterozygosities estimated in previous studies (Zhong et al. 1994; Chiurazzi, Genuardi et al. 1996; Chiurazzi, MacPherson et al. 1996) and DXS548 is slightly higher (Chiurazzi, Genuardi et al. 1996; Chiurazzi, MacPherson et al. 1996).

In agreement with previous studies in Basques (Zhong et al. 1995; Brown et al. 1996), the allele size association between FRAXAC1, DXS548, and CGG repeats is positive. There is significant linkage disequilibrium between CGG repeats and FRAXAC1 alleles 18 and 21 and between CGG repeats and DXS548 alleles 194, 202, and 204.

On fragile X chromosomes in European and Caucasian populations the more frequent alleles were 18 and 21 for FRAXAC1 (Richards et al. 1992; Hirst et al. 1993; Jacobs et al. 1993; MacPherson et al. 1994; Zhong et al. 1994; Chiurazzi, Genuardi et al. 1996; Chiurazzi, MacPherson et al. 1996). In our population these alleles are associated with the largest CGG repeats. In European and Caucasian populations the DXS548 alleles preferably associated with fragile X alleles and with normal chromosomes with large repeat sizes are 204 and 196 (Buyle et al. 1993; Oudet, Morner et al. 1993; Haataja et al. 1994; MacPherson et al. 1994; Malmgren et al. 1994; Zhong et al. 1994, 1996; Chiurazzi, Genuardi et al. 1996, Chiurazzi, MacPherson et al. 1996; Syrrow et al. 1996). In our population allele 204 is significantly associated with the largest repeats and allele 196 is associated in similar percentages with the largest and the smallest repeats, and the differences are not significant.

The association between FRAXAC1/DXS548 haplotypes and CGG repeats is also positive. There is significant linkage disequilibrium between CGG repeats and haplotypes 194/19, 196/18, 202/18, 202/21, and 204/21. The last 4 haplotypes are significantly associated with greater than 31 repeats. These results correspond to those obtained by Zhong et al. (1995). The 2 most prevalent fragile X haplotypes, 196/18 and 204/21 (Chiurazzi, Genuardi et al. 1996; Chiurazzi, MacPherson et al. 1996), are the ones associated in our sample with a higher frequency of the largest repeats for both haplotypes.

According to Zhong et al. (1995), the covariation of CGG and microsatellite polymorphism can be interpreted as an indicator of either a founder effect or an interrelated mutational mechanism such as gene conversion. According to Chiurazzi, Genuardi et al. (1996) and Chiurazzi, MacPherson et al. (1996), the observed high heterozygosity could still be compatible with few founding events if they occurred on different and distant haplotypes, irrespective of their relative frequency in the control population.

In summary, the global analysis of our results indicates, in accordance with Kunst et al.'s (1996) findings, that the prevalence of predisposing normal alleles in the Basque population is 0.00% or close to it. This could be 1 of the explanations of the apparently low fragile X syndrome incidence found in the Basque mentally retarded sample analyzed by us. This low incidence does not seem to be associated with the flanking microsatellite markers. Contrary to what has been found by Syrrow et al. (1996) in Greek and Cypriot populations, our results show that in our population microsatellite markers would not be informative for the indirect diagnosis of fragile X syndrome. Besides, the attributes of the data could be explained by a founder effect. According to Cavalli-Sforza and Piazza (1993), the genetic history of the Basque population favors founder effects.

Acknowledgments This research was supported by the Department of Education, Universities, and Research of the Basque Government. We wish to express our gratitude to J.M. Millan and F. Martinez for their generous assistance. We thank the professionals and institutions who contributed to this project. We are greatly indebted to the probands, the families of the probands, and the Basque people for their kind cooperation in this study.

Received 12 December 1997; revision received 20 April 1998.

Literature Cited

Arinami, T., M. Asano, K. Kobayashi et al. 1993. Data on the CGG repeat at the fragile X site in the nonretarded Japanese population and family suggest the presence of a subgroup of normal alleles predisposing to mutate. Hum. Genet. 92:431-436. Arrieta, M.I., B. Martinez, B. Criado et al. 1990. Dermatoglyphic analysis of autistic Basque children. Am. J. Med. Genet. 35:1-9.

Arrieta, M.I., B. Martinez, J.M. Millan et al. 1997. Study of a trimeric tandem repeat locus (SBMA) in the Basque population: Comparison with other populations. Gene Geogr. 11:61-72.

Arrieta, M.I., T. Nunez, A. Gil et al. 1996. Autosomal folate sensitive fragile sites in autistic Basque sample. Ann. Genet. 39(2):69-74.

Ashley, C.T., and S.T. Warren. 1995. Trinucleotide repeat expansion and human disease. Annu. Rev. Genet. 29:563-566.

Brown, W.T., and E.C. Jenkins. 1992. The fragile X syndrome. In Molecular Genetic Medicine, T. Friedmann, ed. San Diego, CA: Academic Press, 39-66. Brown, W.T., N. Zhong, and C. Dobkin. 1996. Positive fragile X microsatellite associations point to a common mechanism of dynamic mutation evolution. Am. J. Hum. Genet. 58(3):641643.

Brown, W.T., G.E. Houck, A. Jeziorowska et al. 1993. Rapid fragile X carrier screening and prenatal diagnosis using a nonradioactive PCR test. J. Am. Med. Assoc. 270(13):15691575.

Buyle, S., E. Reyniers, L. Vits et al. 1993. Founder effect in a Belgian-Dutch fragile X population. Hum. Genet. 92:269-272.

Cavalli-Sforza, L.L., and A. Piazza. 1993. Human genomic diversity in Europe: A summary of recent research and prospect for the future. Eur. J. Hum. Genet. 1:3-18. Chiurazzi, P., M. Genuardi, L. Kozak et al. 1996. Fragile X founder chromosomes in Italy: A few initial events and possible explanation for their heterogeneity. Am. J. Med. Genet. 64:209-215.

Chiurazzi, P., J. MacPherson, S. Sherman et al. 1996. Significance of linkage disequilibrium between the fragile X locus and its flanking markers. Am. J. Med. Genet. 64:203-208. Eichler, E.E., and D.L. Nelson. 1996. Genetic variation and evolutionary stability of the FMR1 CGG repeat in six closed human populations. Am. J. Med. Genet. 64:220-225. Eichler, E.E., J.J.A. Holden, B.W. Popoich et al. 1994. Length of interrupted CGG repeats determines stability in the FMR1 gene. Natur. Genet. 8:88-94. Eichler, E.E., C.B. Kunst, K.A. Lugenbeel et al. 1995. Evolution of cryptic FMR1 CGG repeat. Natur. Genet. 11:301-308.

Fu, Y.H., D.P.A. Kuhl, A. Pizzuti et al. 1991. Variation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Shermen paradox. Cell 67:1047-1058. Gabarron, J., I. Lopez, G. Glover et al. 1992. Fragile X screening program in Spanish region. Am. J. Med. Genet. 43:333-338.

Haataja, R., M.L. Vaisanen, M. Li et al. 1994. The fragile X syndrome in Finland: Demonstration of a founder effect by analysis of microsatellite haplotypes. Hum. Genet. 94:479483.

Hashimoto, O., Y. Shimizu, and Y. Kawasaki. 1993. Brief report: Low frequency of the fragile X syndrome among Japanese autistic subjects. J. Autism Dev. Disord. 23(1):201-209. Heitz, D., D. Devys, G. Imbert et al. 1992. Inheritance of the fragile X syndrome: Size of the fragile X premutation is a major determinant of the transition to full mutation. J. Med. Genet. 29:794-801.

Hirst, M.C., P.K. Grewal, and K.A. Davies. 1994. Precursor arrays for triplet repeat expansion

at the fragile X locus. Hum. Molec. Genet. 3:1553-1560.

Hirst, M.C., S.J.L. Knight, Z. Christodoulou et al. 1993. Origin of fragile X syndrome mutation. J. Med. Genet. 30:647650.

Howard-Peebles, P.N., and G.R. Stoddard. 1980. Race distribution in X-linked mental retardation with macro-orchidism and fragile site in Xq. Am. J. Hum. Genet. 32:629-630. Jacobs, P.A., H. Bullman, J. MacPherson et al. 1993. Population studies of the fragile X: A

molecular approach. J. Med. Genet. 30:454-459.

Kremer, E.J., S. Yu, M. Pritchard et al. 1991. Isolation of a human DNA sequence which spans the fragile X. Am. J. Hum. Genet. 49:656-661.

Kunst, C.B., and S.T. Warren. 1994. Cryptic and polar variation of the fragile X repeat could

result in predisposing normal alleles. Cell 77:853-861. Kunst, C.B., C. Zerylnick, L. Karickhoff et al. 1996. FMR1 in global population. Am. J. Hum. Genet. 58(3):513-522.

Lubs, H.A. 1969. A marker X chromosome. Am. J. Hum. Genet. 21:231-244. MacPherson, J.N., H. Bullman, S.A. Youings et al. 1994. Insert size and flanking haplotype in fragile X and normal population: Possible multiple origins for the fragile X mutation. Hum. Molec. Genet. 3(3):399X05.

Malmgren, H., K.H. Gustavson, C. Oudet et al. 1994. Strong founder effect for the fragile X

syndrome in Sweden. Eur. J. Hum. Genet. 2:103-109.

Martin, J.P., and J. Bell. 1943. A pedigree of mental defect showing sex linkage. J. Neurol. Psychiatr. 6:151-154.

Martinez, F. 1994. Estudio genetico del sindrome del cromosoma X fragil y otras formas de retraso mental inespecffico ligado al X. Doctoral thesis, University of Valencia, Valencia, Spain.

McKeigue, P.M. 1997. Mapping genes underlying ethnic differences in disease risk by linkage disequilibrium in recently admixed populations. Am. J. Hum. Genet. 60:188-196. Morton, N.E., and J.N. MacPherson. 1992. Population genetics of the fragile X syndrome: A

multiallelic model for the FMR1 locus. Proc. Natl. Acad. Sci. USA 89:4215-4217. Nei, M. 1978. Estimation of average heterozygosity and genetic distance from a small number of individuals. Genetics 89:583-590. Nelson, D.L. 1995. The fragile X syndrome. Cell 6:5-11.

Oberle, I., F. Rousseau, D. Heitz et al. 1991. Instability of a 550-base pair DNA segment and

abnormal methylation in fragile X syndrome. Science 252:1097-1102. Odelberg, S.J., R. Plaetke, J.R. Eldridge et al. 1989. Characterization of eight VNTR loci by agarose gel electrophoresis. Genomics 5:915-924.

Oudet, C., E. Mornet, J.L. Serre et al. 1993. Linkage disequilibrium between the fragile X mutation and two closely linked CA repeats suggests that fragile X chromosomes are derived from a small number of founder chromosomes. Am. J. Hum. Genet. 52:297-304. Oudet, C., H. von Koskull, A.M. Nordstrom et al. 1993. Striking founder effect for the fragile

X syndrome in Finland. Eur. J. Hum. Genet. 1:181-189. Rhoads, F.A. 1984. Fragile X syndrome in Hawaii: A summary of clinical experience. Am. J. Med. Genet. 17:209-214.

Richards, R.I., K. Holman, K. Friend et al. 1992. Evidence of founder chromosomes in fragile X syndrome. Natur. Genet. 1:257-260.

Richards, R.I., K. Holman, E. Kremer et al. 1991. Fragile X syndrome: Genetic localization by linkage mapping of two microsatellite repeats FRAXAC1 and FRAXAC2 which immediately flank the fragile site. J. Med. Genet. 28:818-823. Riggins, G.J., S.L. Sherman, B.A. Oostra et al. 1992. Human genes containing polymorphic trinucleotide repeats. Natur. Genet. 2:186-191.

Rivera, H., L. Hernandez, J. Plascenia et al. 1981. Some observations on the mental deficiency of normo-functional testicular hyperplasia and fra(X) (q28) chromosome syndrome. Ann. Genet. 24:220-222.

Rousseau, F., P. Rouillard, M.L. Morel et al. 1995. Prevalence of carriers of premutation size alleles of the FMRI gene and implications for the population genetics of the fragile X syndrome. Am. J. Hum. Genet. 57:1006-1018.

Sherman, S.L. 1995. The high prevalence of fragile X premutation carrier females: Is this frequency unique to the French Canadian population? Am. J. Hum. Genet. 57:991-993. Snow, K., L.K. Doud, R. Hagerman et al. 1993. Analysis of the CGG sequence at the FMR] locus in the fragile X families and in general population. Am. J. Hum. Genet. 53:12171228.

Snow, K., D.J. Tester, K.E. Kruckeberg et al. 1994. Sequence analysis of the fragile X trinucleotide repeat: Implications for the origin of the fragile X mutation. Hum. Molec. Genet. 3(9):1543-1551.

Soysa, P., M. Senanayahe, M. Mikkelsen et al. 1982. Martin-Bell syndrome fra(X) (q28) in a Sri Lankan family. J. Ment. Defic. Res. 26:251-257.

Syrrow, M., P.C. Patsalis, I. Georgiou et al. 1996. Evidence for high risk haplotypes and (CGG)n expansion in the fragile X syndrome in the Hellenic population of Greece and Cyprus. Am. J. Med. Genet. 64:234-238.

Turner, G., T. Webb, S. Wake et al. 1996. Prevalence of fragile X syndrome. Am. J. Med. Genet. 64:196197.

Tzipora, C.F.Z., E. Shanchak, M. Yalon et al. 1997. Predisposition to the fragile X syndrome in Jews of Tunisian descent is due to absence of AGG interruptions on a rare Mediterranean haplotype. Am. J. Hum. Genet. 60:103-112.

Venter, P.A., G.S. Gericke, B. Dawson et al. 1981. A marker X chromosome associated with nonspecific male mental retardation. S. Afr. Med. J. 21:807-811. Verkerk, A.J.M.H., M. Pieretti, J.S. Sutcliffe et al. 1991. Identification of a gene (FMRI) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65:905-914.

Wallace, D.C., and A. Torroni. 1992. American Indian prehistory as written in the mitochondrial DNA: A review. Hum. Biol. 64:403416.

Yu, S., J. Mulley, D. Loesch et al. 1992. Fragile X syndrome: Unique genetics of the heritable unstable element. Am. J. Hum. Genet. 50:968-980.

Yu, S., M. Pritchard, E. Kremer et al. 1991. Fragile X genotype characterized by an unstable

region of DNA. Science 252:1179-1181.

Zar, J.H. 1996. Biostatistical Analysis, 3d ed. Englewood Cliffs, NJ: Prentice Hall. Zerylnick, C., A. Torroni, S.L. Sherman et al. 1995. Normal variation at the myotonic dystrophy

locus in global human population. Am. J. Hum. Genet. 56:123-130. Zhong, N., E. Kajanija, B. Smits et al. 1996. Fragile X founder effects and new mutations in Finland. Am. J. Med. Genet. 64:226-233.

Zhong, N., W. Yang, C. Bobkin et al. 1995. Fragile X gene instability: Anchoring AGGs and

linked microsatellites. Am. J. Hum. Genet. 57(2):351-361. Zhong, N., L. Ye, C. Dobkin et al. 1994. Fragile X founder chromosome effects: Linkage disequilibrium or microsatellite heterogeneity. Am. J. Med. Genet. 51:417-422.

I. ARIET,1 A. GIL.1 T. NUNEZ,1 M. TELEZ.1 B. MARTINEZ,1 B. CRIADO,2,3 AND C. LOSTAO1

1 Departamento de Biologia Animal y Genetica, Facultad de Ciencias, Universidad del Pars Vasco, Apartado 644, 48080 Bilbao, Spain.

2 Instituto de Patologia e Imunologia Molecular, Universidad do Porto (IPATIMUP), Rua Dr. Roberto Frias s/n, 4200 Porto, Portugal.

3 Instituto Superior da Maia, S. Pedro Avioso, Castelo Maia 4470, Portugal.

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