Abstract
In order to investigate the stability of the FMR1 (Fragile X Mental Retardation 1) alleles from the normal population, when maternally inherited, we analyzed 75 mother-to-son transmissions. Sixty-eight alleles fell within the common range with 20-40 CGG repeats, and seven alleles were intermediate, with 41-48 repeats. No change was observed either in the length or in the structure of these repeats upon transmission. Fifty-three alleles were ascertained in different families, and their size distribution was similar to those described for European and European-derived populations, with three peaks of frequency: 66% of the alleles with (CGG)29, (CGG)30 or (CGG)31, 7.5% with (CGG)20, and 5.7% with (CGG)23. Regarding the AGG interspersion pattern, 69.8% had two AGG repeats, 20.8% had one, 5.7% had three and 3.8% had none. The most common patterns were 10+9+9 (30.2%), 9+9+9 (18.9%), 10+9 (7.5%), and 10+9+10 (7.5%). About 70% of the alleles with up to 40 repeats were linked to the DXS548/FRAXAC1 haplotype 7-3, the most commonly reported in normal populations. Four out of five intermediate alleles were in linkage with the two haplotypes most frequently associated to the FMR1 full mutation, 2-1 and 6-4. These four alleles showed long uninterrupted CGG repeats at the 3' end. The 9+9+22, 9+9+23 and 9+9+28 alleles were linked to the haplotype 2-1, and the 9+37 allele, to the haplotype 6-4. The pattern of AGG interspersion of these alleles and the associated haplotypes were in accordance with the two main pathways toward mutation previously proposed.
Highlights
The fragile X syndrome is the most common Xlinked mental retardation disorder affecting ~1 in 4,000 males and ~1 in 8,000-9,000 females (Crawford et al., 2001)
The number and position of AGG interspersions determining long uninterrupted CGG arrays at the 3’ or 5’ ends of the repeat, haplotype background and parental origin have been evoked as predisposing factors leading a common/intermediate allele to progress toward a mutation state
The stability of the Fragile-X Mental Retardation 1 gene (FMR1) CGG repeat was evaluated in 75 mother-son transmissions: 46 mother-one son, 11 mother-two son (22), one mother-three son (3), and one mother-four son (4) transmissions
Summary
The fragile X syndrome is the most common Xlinked mental retardation disorder affecting ~1 in 4,000 males and ~1 in 8,000-9,000 females (Crawford et al., 2001). Alleles with repeats in the ~55-200 range, which are transcribed, but unstable, may expand to full mutations upon maternal transmission Which includes high-common and low-premutation alleles (Eichler et al, 1994) These intermediate alleles are defined as those with 41~60 repeats, which may or may not be inherited in an unstable manner. The number and position of AGG interspersions determining long uninterrupted CGG arrays at the 3’ or 5’ ends of the repeat, haplotype background and parental origin have been evoked as predisposing factors leading a common/intermediate allele to progress toward a mutation state
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