Mosaicism in fragile X affected males

Abstract

Fragile X affected males have an expansion of a CGG repeat and a hypermethylated CpG island 5' to the FMR-1 gene. Mosaic males with both a premutation and full mutation have been noted among the affected individuals. Such mosaic males are most easily identified by the presence of a methylated restriction fragment characteristic of the full mutation and an additional unmethylated fragment in the premutation range in Southern analyses with EcoR I and the methylation-sensitive enzyme Eag I and a probe such as StB12.3. We analyzed a group of affected fragile X males by Southern blotting and found 41% (61/148) to be mosaic. The 148 individuals were divided between 36 pairs of brothers and 76 unrelated males. Little difference in the number of mosaics was seen between the brothers and the unrelated males nor was the expected distribution of mosaicism in brother pairs different from observed. Thus, these data do not suggest a familial basis for mosaicism. Our observation that 41% affected fragile X males were mosaic is significantly higher than previous reports. The difference is likely due to technical modifications which permitted the identification of faint premutation bands in some patients. The high percentage of affected males with mosaicism seen here suggests that the occurrence of such individuals may be a much more frequent event than presently recognized.

Comparative analysis of DNA methylation in transgenic mice with unstable CGG repeats from FMR1 gene

“…10 The instability is associated with unmethylated CGG repeats while large also as the stable allele with 26 repeats is detected in the transgenic mice along with alleles with expanded CGG repeats as seen in several human patients. [28][29][30][31] It remains to be seen if stability and methylation are correlated in these transgenic mice. In an earlier report in human patients mosiacism in repeat number was correlated with the absence of DNA methylation.…”

Attentional dysfunction, impulsivity, and resistance to change in a mouse model of fragile X syndrome.

“…A minority of individuals with FXS have a mosaic pattern with some cells showing sizes of less than 200 repeats and partially active gene expression . Methylation mosaicism has also been shown in affected individuals such that a full mutation shows only partial methylation (Nolin et al, 1994). It has been known that mosaicism is correlated with a less severe phenotype and a better prognosis of this disorder (McConkie-Rosell et al, 1993;Cohen et al, 1996).…”

“…For example, the brothers of males with full mutations are less likely to be affected than the sons of their daughters. Furthermore, it has been shown that there is a strong familial clustering of repeat size expansion such that the offspring of some female carriers tend to have the full mutation, whereas those of other female carriers tend to be only premutations (Nolin et al, 1994(Nolin et al, , 1996. Individuals with fewer than 60 repeats have never been found to have had affected male children.…”

PresynapticFmr1Genotype Influences the Degree of Synaptic Connectivity in a Mosaic Mouse Model of Fragile X Syndrome

“…In female patients, X-inactivation silences either the mutant or normal X chromosome in each cell, resulting in mosaic FMRP expression, with variable skewing of X inactivation leading to variability in the percentage of cells expressing FMRP (Martínez et al, 2005). In addition, variable silencing of the FMR1 gene in different cells, can results in mosaic expression of FMRP in some male patients (Pieretti et al, 1991;Nolin et al, 1994;Rousseau et al, 1994).…”