Translocation (X;20)(q13;q13.3): a nonrandom abnormality in four patients with myeloid disorders.

A recurring translocation (X;20)(q13;q13) was found in four women ranging in age from 57 to 77 years. They had myelodysplasia, myelodysplasia with thrombocytopenia and pancytopenia, transforming to myelofibrosis, and myelodysplasia with sideroblastic anemia, respectively. The t(X;20) was the sole abnormality in three cases; one case also had a der(1;7)(q10;p10). Added to three previously reported cases, our four cases bring the total to seven; thus, t(X;20)(q13;q13) is a nonrandom translocation associated with myeloid disorders. Previous FISH studies showed that the breakpoint on the X is proximal to XIST. In one of our cases, the breakpoint on the X was shown to be proximal to Xq12, by FISH using a probe for the androgen receptor gene locus.

Folate-sensitive fragile site FRA10A is due to an expansion of a CGG repeat in a novel gene, FRA10AC1, encoding a nuclear protein.

Fragile sites appear visually as nonstaining gaps on chromosomes that are inducible by specific cell culture conditions. Expansion of CGG/CCG repeats has been shown to be the molecular basis of all five folate-sensitive fragile sites characterized molecularly so far, i.e., FRAXA, FRAXE, FRAXF, FRA11B, and FRA16A. In the present study we have refined the localization of the FRA10A folate-sensitive fragile site by fluorescence in situ hybridization. Sequence analysis of a BAC clone spanning FRA10A identified a single, imperfect, but polymorphic CGG repeat that is part of a CpG island in the 5'UTR of a novel gene named FRA10AC1. The number of CGG repeats varied in the population from 8 to 13. Expansions exceeding 200 repeat units were methylated in all FRA10A fragile site carriers tested. The FRA10AC1 gene consists of 19 exons and is transcribed in the centromeric direction from the FRA10A repeat. The major transcript of approximately 1450 nt is ubiquitously expressed and codes for a highly conserved protein, FRA10AC1, of unknown function. Several splice variants leading to alternative 3' ends were identified (particularly in testis). These give rise to FRA10AC1 proteins with altered COOH-termini. Immunofluorescence analysis of full-length, recombinant EGFP-tagged FRA10AC1 protein showed that it was present exclusively in the nucleoplasm. We show that the expression of FRA10A, in parallel to the other cloned folate-sensitive fragile sites, is caused by an expansion and subsequent methylation of an unstable CGG trinucleotide repeat. Taking advantage of three cSNPs within the FRA10AC1 gene we demonstrate that one allele of the gene is not transcribed in a FRA10A carrier. Our data also suggest that in the heterozygous state FRA10A is likely a benign folate-sensitive fragile site.