Fragile X founder chromosomes in Italy: A few initial events and possible explanation for their heterogeneity

Chiurazzi, Pietro; Genuardi, Maurizio; Kozák, Libor; Giovannucci-Uzielli, M. L.; Bussani, Cecilia; Dagna-Bricarelli, F; Grasso, Marina; Perroni, L; Sebastio, Gianfranco; Sperandeo, Maria Pia; Oostra, Ben A.; Neri, Giovanni

doi:10.1002/(sici)1096-8628(19960712)64:1<209::aid-ajmg38>3.0.co;2-p

Cited by 42 publications

(42 citation statements)

References 55 publications

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“…In agreement with other studies, [21][22][23][24][25][26][27][28][29] A-2 and D-6 were also highly prevalent in our sample (38% of patients), supporting the contention that these two haplotypes are present on ancestral European fragile X founder chromosomes. 28,29 The presence of haplotypes C-2 and C-5 in 16 (38%) fragile X chromosomes, suggests the existence of specific founder mutations in Portuguese patients, since no similar findings have been observed in other populations.…”

Section: Discussionsupporting

confidence: 93%

“…28,29 The frequency of haplotype C-7 in normal chromosomes was significantly higher than that expected from the corresponding allele frequencies. This finding may indicate the existence of linkage disequilibrium between the two markers and/or the selective advantage of this haplotype when associated with the normal FMR1 gene as compared to C-7 fragile X chromosomes.…”

Section: Discussionmentioning

confidence: 74%

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Analysis of FMR1 and flanking microsatellite markers in normal and fragile X chromosomes in Portugal: evidence for a “protector” haplotype

et al. 1998

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In order to look for linkage disequilibrium between the fragile X locus and its flanking markers, we analysed the FRAXAC1 and DXS548 microsatellites in normal and fragile X individuals of Portuguese origin. We observed differences in allele and haplotype frequencies between these two samples. Four haplotypes (A-2, C-2, C-5 and D-6) accounted for 76% of all fragile X chromosomes, whereas a single haplotype (C-7) accounted for 70% of the normal population and less than 3% of the fragile X chromosomes. Among the four observed high-risk haplotypes, A-2 and D-6 had been previously reported in other studies, but C-2 and C-5 seem characteristic of Portuguese patients, as suggested by the high frequency (38%) in fragile X chromosomes and virtual absence in controls. In accordance with previous studies, a greater heterozygosity of the fragile X sample was noted when compared to that of controls. The high frequency of C-7 haplotype in the normal population and its virtual absence in the fragile X sample may reflect the existence of linkage disequilibrium between the two loci and/or selective advantage (protector effect) of this haplotype.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 74%

Analysis of FMR1 and flanking microsatellite markers in normal and fragile X chromosomes in Portugal: evidence for a “protector” haplotype

et al. 1998

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“…The DXS548 polymorphism was detected by a modified PCR method (Riggins et al, 1992) using primers described by Chiurazzi et al (1996a). Consistency of allele denomination was ensured by typing control DNAs kindly provided by Dr JN Macpherson (Salisbury Hospital, Salisbury, England) and by Dr K Grnskov (The John F Kennedy Institute, Glostrup, Denmark).…”

Section: Dna Analysesmentioning

confidence: 99%

“…DXS548 (Riggins et al, 1992) and FRAXAC1 , two dinucleotide (CA) repeat markers 150 and 7 kb, respectively, proximal to the CGG repeat, have been the most characterized marker loci used in association studies. Haplotype construction with these markers has revealed linkage disequilibrium between the normal, stable alleles as well as the unstable CGG repeat alleles among individuals with fragile X syndrome in studies of European populations from France and Spain (Oudet et al, 1993a), Belgium and the Netherlands (Buyle et al, 1993), Northern Europe (Riggins et al, 1992), Italy (Chiurazzi et al, 1996a), United Kingdom (Macpherson et al, 1994), Sweden (Malmgren et al, 1994), Finland (Oudet et al, 1993b;Haataja et al, 1994;Zhong et al, 1996), Greece and Cyprus (Patsalis et al, 1999) and Denmark (Larsen et al, 1999(Larsen et al, , 2000.…”

Section: Introductionmentioning

confidence: 99%

The FMR1 CGG repeat and linked microsatellite markers in two Basque valleys

et al. 2003

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Fragile X syndrome is associated with an unstable CGG repeat sequence in the 5 0 untranslated region of the first exon of the FMR1 gene. The present study involved the evaluation of factors implicated in CGG repeat stability in a normal sample from two Basque valleys (Markina and Arratia), to discover whether the Basque population shows allelic diversity and to identify factors involved, by using the data in conjunction with previous findings. The study was based on a sample of 204 and 58 X chromosomes from the Markina and Arratia valleys, respectively. The CGG repeat, the AGG interspersion and two flanking microsatellite markers, FRAX-AC1 and DXS548, were examined. In the Markina valley, gray zone alleles (X35 CGG repeats) were associated with anchoring AGGs, with the longest 3 0 pure CGG repeats of the valley ( ¼ 15), with the 5 0 instability structure 9+n and with one principal fragile X FRAXAC1-DXS548 haplotype 42-50. In the Arratia valley, gray zone alleles (X35 CGG repeats) showed the highest frequency among the Basque samples analyzed, and were associated with anchoring AGGs, with the longest 3 0 pure repeats (X20), with the 5 0 instability structure 9+n and with one 'normal' FRAXAC1-DXS548 haplotype 38-40 (these data from Arratia suggest the existence of a 'protective' haplotype). The results showed, on the one hand, differences between Markina and Arratia in factors implicated in CGG repeat instability and, on the other hand, a great similarity between the general Basque sample from Biscay and the Markina valley.

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“…No trend in this direction was observed, since the distribution of the haplotypes in premutation women with POF did not characterize their families as a subset of fragile X families. Indeed, 60% of the premutation carriers with POF had the haplotypes most commonly observed on the fragile X chromosomes in Brazilian families as well as in other populations (Chiurazzi et al, 1996). Therefore, no indication was found that the POF-associated premutations had a specific origin or resided on a particular haplotype background.…”

Section: Discussionmentioning

confidence: 98%

The FMR1 premutation as a cause of premature ovarian failure in Brazilian women

et al. 2006

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The loss-of-function mutation of the FMR1 gene due to expansion of the 5' UTR CGG repeat causes the fragile X syndrome, the most frequent form of inherited mental retardation. On the other hand, the FMR1 premutation, which is transcriptionally active and produces the protein, confers an increased risk for premature ovarian failure (POF) to carrier females. Among 41 unrelated Brazilian women with idiopathic POF, we found three carriers of premutations (CGG expansionse ³ 59 repeats) and two carriers of high-intermediate alleles (50-55 repeats). Two premutations and two intermediate alleles were detected among the 16 familial POF cases, and one premutated woman, among the 25 sporadic cases. The premutation frequency among the familial cases (12.5%) differed significantly from that found in a control group of 96 unrelated Brazilian women aged ³ 47 years, who had not experience POF and in which no premutations or high-intermediate alleles were detected. In the search for factors influencing the probability of a premutation carrier presenting POF, another 20 unrelated premutated women with POF, from fragile X families, were included in the study. The analysis of the FMR1-linked loci DXS548 and FRAXAC1 did not indicate any association of a particular haplotype with the occurrence of POF. An effect of X-inactivation skewing was not apparent in blood cells, and POF-associated premutations showed a wide range of repeat sizes, from 59, the smallest known to expand to full mutations upon transmission to offspring, to approximately 200.

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Fragile X founder chromosomes in Italy: A few initial events and possible explanation for their heterogeneity

Cited by 42 publications

References 55 publications

Analysis of FMR1 and flanking microsatellite markers in normal and fragile X chromosomes in Portugal: evidence for a “protector” haplotype

Analysis of FMR1 and flanking microsatellite markers in normal and fragile X chromosomes in Portugal: evidence for a “protector” haplotype

The FMR1 CGG repeat and linked microsatellite markers in two Basque valleys

The FMR1 premutation as a cause of premature ovarian failure in Brazilian women

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