FRAXE mutation analysis in three spanish families

Abstract

Very little is known about the phenotype of FRAXE‐positive individuals and the relation between the genotype/phenotype and genotype/cytogenetic expression. We describe three families with normal and mildly affected individuals and a severely retarded male expressing fragility at the FRAXE locus or presenting different expansions at the CGG FRAXE triplet. In addition, we analyze the FRAXE mutation in sperm DNA from a retarded male carrier with a handicapped daughter expressing fragility at the FRAXE locus. Mental status in FRAXE individuals is highly variable and, although mild mental retardation is observed in most cases, several carrier males are apparently normal. It seems that methylation is not as strictly associated with size of CGG triplets in the FRAXE locus as in FRAXA, and it is possible that normal carrier individuals with fully methylated increments in lymphocytes have a certain proportion of unmethylated alleles in the critical (i.e., neural) tissues. FRAXE mutation is apparently similar to FRAXA in that males with somatic large methylated increments are carriers of small unmethylated ones in germinal cells. © 1996 Wiley‐Liss, Inc.

FRAXE mutation in a mentally retarded subject and in his phenotypically normal twin brother

“…Other two clinically normal individuals were reported to have the FRAXE CpG island 100% methylated and, as a consequence, a transcriptionally silent FRM2 gene. [6][7][8]10 Similar cytogenetically positive, fully methylated but unaffected males have been described by Knight 4 and Murgia; 27 although FMR2 expression was not tested. That could be explained considering that clinical variability may arise if the severity of the FRAXE MR phenotype is compensated by modifying factors present in the genetic background or if the effect of the FRAXE mutation is so mild that the phenotype can remain within the normal range in some subjects.…”

“…Further studies on additional families co-segregating MR and the FRAXE fragile site suggested that an etiological relationship may exist between FRAXE and mild non-specific X-linked MR. [4][5][6][7] The relationship was difficult to establish in the absence of a phenotype other than mild (or borderline) nonspecific MR. Screening programs in different candidate populations of mentally impaired boys detected no [19][20][21] or only a few cases of FRAXE MR. [22][23][24][25] Based on these studies, the prevalence of FRAXE was estimated to be approximately 1:50000 males.…”

“…Considering this, the phenotype of our patient seems to be unusual since mental retardation is severe and dysmorphic features are striking, although Marfan-like habitus, long narrow face, high arched palate and midface hypoplasia have been previously reported in FRAXE patients. 28,29 Uncertainty about genotype-phenotype correlation in FRAXE-associated MR, resulting from the mild phenotypic effect, the low incidence and the low rate of detection of new cases from large candidate population studies, the variable phenotype of the carrier females and the different size of the expansions transmitted from fully mutated fathers to daughters [5][6][7]26 greatly limits the actual possibility of predicting phenotypes in males and females with the mutation and offering prenatal diagnosis to FRAXE families.…”

“…3 Several families have been described, in whom expression of the FRAXE fragile site and mental retardation (MR) segregate. [4][5][6][7] Recently, a gene associated to FRAXE and designed as FMR2 has been cloned and shown to be expressed in brain and placenta. 8,9 Loss of FMR2 expression seems to correlate with (GCC) n expansion at FRAXE, suggesting the involvement of this gene in FRAXE-associated mild MR. [8][9][10] However, a few phenotypically normal males have been reported with complete methylation at the FRAXE locus and no FMR2 expression.…”

Pathogenic expansions of the SCA6 locus are associated with a common CACNA1A haplotype across the globe: founder effect or predisposing chromosome?

“…20,21 CpG methylation may also influence trinucleotide repeat tract stability through an effect on chromosomal structure. 24,25 We therefore used a bioinformatic approach using a previously described method to study GC content flanking other trinucleotide repeat genes. 26,27 Genomic sequence for 5000 bp upstream and 5000 bp downstream of the CACNA1A (CAG) n repeat sequence were downloaded from NCBI and analyzed using cpgplot (available through EMBOSS) in the 5 0 -3 0 orientation, with a moving window of 500 bp and a step of 100 bp.…”