High functioning fragile X males: Demonstration of an unmethylated fully expanded FMR‐1 mutation associated with protein expression

Abstract

Fragile X (fra(X)) males with a standardized IQ score of 70 or higher represent a high functioning (HF) or nonretarded fra(X) male group. This group, which does not include nonpenetrant males, has received little research attention to date. Of 221 fra(X) males who had been evaluated through The Children's Hospital in Denver since 1981 and had completed cognitive or developmental testing, 29 (13%) were high functioning by the above definition. We found that HF males on the whole had a lower cytogenetic score and were younger than retarded fra(X) males, but there was no difference between these two groups in the number of typical fra(X) physical manifestations present. FMR-1 DNA testing was performed on 134 fra(X) males and methylation status was determined for 51 of these. A greater percentage of HF males had a mosaic pattern or an incompletely methylated full mutation than did retarded males. A unique DNA pattern, an unmethylated fully expanded mutation, was discovered in 3 of the highest functioning fra(X) males. Protein studies performed on 2 of these males demonstrated the presence of FMR-1 protein, albeit at lower levels than normal. FMR-1 protein was not present in retarded fra(X) males. Significant FMR-1 protein expression may be responsible for higher cognitive functioning in the 2 males with unmethylated fully expanded mutations compared to retarded fra(X) males.

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.…”

“…35 Variable methylation correlated with higher levels of FMR1 transcription is reported in high functioning fragile X males who have higher IQ than typical fragile X patients. 10 Further it is known, that variable methylation of FMR1 locus is responsible for phenotypic variation in fragile X patients.…”

“…8 Although in most cases FMR1 full mutation alleles are hypermethylated, unmethylated alleles in the full mutation range have also been described and are generally associated with a less severe phenotype. [8][9][10][11][12][13] However methylation in absence of repeat expansion leading to fragile X syndrome is not reported so far.…”

Hotspot for deletions in the CGG repeat region of FMR1 in fragile X patients

“…Disappearance of the full mutation would then result in passive déméthylation. Méthylation being an active mechanism might explain the occurrence of unmethylated full mutations (36). The possibility that déméthylation is an active process in itself, causing the deletion by, for instance, nicking, can not be excluded.…”

Incomplete penetrance and variable expressivity: is there a microRNA connection?

“…(25) The length of CGG repeat in the 5 0 UTR of fragile X mental retardation gene (FMR1) is also tightly correlated with methylation of the promoter and hence transcription of the gene. (26) Apart from epigenetic regulation, the number of genetic lesions and nature of functional domain altered by mutation or polymorphism may contribute to phenotypic variability in complex diseases. The loss of canonical splice site by a single base change in the RET gene, a receptor tyrosine kinase in Hirschsprung disease (aganglionic megacolon), results in the absence of expression of functional protein and the severity of the disease is related to the homozygosity of the mutation.…”