Structure and stability upon maternal transmission of common and intermediate FMR1 (Fragile X Mental Retardation 1) alleles in a sample of the Brazilian population

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.

Frequency of FMR1 premutation in individuals with ataxia and/or tremorand/or parkinsonism

“…The most frequent alleles were those ranging from 28 to 30 CGG repeats, which is in good agreement with previous descriptions in the literature (Capelli et al, 2005;Willemsen et al, 2005;Van Esch, 2006). Gray zone alleles were detected among patients as well as in the control group with frequencies of 3.03 and 2.70%, respectively (P = 0.38, Fisher exact test).…”

“…Fragile X syndrome frequency varies from 1:4000 to 1:6000 men in Caucasian populations (Martin et al, 1980;Richards et al, 1981;Flannery et al, 1995;Turner et al, 1996;de Vries et al, 1997de Vries et al, , 1999Capelli et al, 2005;Van Esch, 2006).…”

“…There is also some discussion in the literature concerning where to set the boundaries between normal size and gray zone and between gray zone and premutation size. Usually, FMR1 phenotype is produced by the expansion of CGG repeats, while loss of FMR1 function due to point mutations has seldom been reported (Jin and Warren, 2003;Leehey et al, 2003;Oostra and Willemsen, 2003;Mandel and Biancalana, 2004;Capelli et al, 2005).…”