Implications of FRA16A Structure for the Mechanism of Chromosomal Fragile Site Genesis

Abstract

Fragile sites are chemically induced nonstaining gaps in chromosomes. Different fragile sites vary in frequency in the population and in the chemistry of their induction. DNA sequences encompassing and including the rare, autosomal, folate-sensitive fragile site, FRA16A, were isolated by positional cloning. The molecular basis of FRA16A was found to be expansion of a normally polymorphic p(CCG)n repeat. This repeat was adjacent to a CpG island that was methylated in fragile site-expressing individuals. The FRA16A locus in individuals who do not express the fragile site is not a site of DNA methylation (imprinting), which suggests that the methylation associated with fragile sites may be a consequence and not a cause of their genesis.

DNA Methylation and Trinucleotide Repeat Expansion Diseases

“…Seven folate-sensitive fragile sites have been identified within human chromosomes: FRAXA , FRAXE (Knight et al, 1993), FRAXF (Parrish et al, 1994), FRA10A (Sarafidou et al, 2004), FRA11B (Jones et al, 1995), FRA12A (Winnepenninckx et al, 2007) and FRA16A (Nancarrow et al, 1994) (Table 1). In each case, the fragile site is associated with a large non-coding CGG repeat expansion, together with methylation of the CpG sites within the repeat expansion as well as within an adjacent upstream CpG island (Lopez Castel et al, 2010a).…”

Molecular characterization of a common fragile site ( FRA7H ) on human chromosome 7 by the cloning of a simian virus 40 integration site

“…The instability of fragile sites at the molecular and cytogenetic levels can lead to disease manifestation by silencing adjacent gene(s) (2,3) or by causing chromosomal rearrangements and disrupting gene expression (4). Several rare fragile sites have been characterized at the molecular level by positional cloning using families expressing these sites (4)(5)(6)(7)(8)(9). The expression of these sites is associated with expanded CGG trinucleotide repeats or with an expanded 33-bp AϩT-rich minisatellite repeats.…”

Identification and Chromosomal Localization of Human Genes Containing CAG/CTG Repeats Expressed in Testis and Brain

“…Expansions of various types of these trinucleotide repeats have been implicated in genetic diseases. Although CGG and GAA repeats are expanded in different fragile X syndromes Verkerk et al 1991;Yu et al 1991;Knight et al 1993;Jones et al 1994;Nancarrow et al 1994;Parrish et al 1994) and Friedreich's ataxia, respectively (Campuzano et al 1996), CTG and CAG repeats are involved in a larger series of pathologies. Amplification of CTG repeats have been described in myotonic dystrophy (MD) (Aslanidis et al 1992;Brook et al 1992;Fu et al 1992), whereas amplifications of CAG repeats have been observed in spinal and bulbar muscular atrophy (SBMA) (La Spada et al 1991), spinocerebellar ataxia type 1 (SCA1) ), Huntington's disease (HD) (The Huntington's Disease Collaborative Research Group et al 1993), dentatopallidoluisian atrophy (DRPLA) (Koide et al 1994;Nagafuchi et al 1994), Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD or SCA3) (Kawagushi et al 1994), spinocerebellar ataxia type 2 (SCA2) (Imbert et al 1996;Pulst et al 1996;Sanpei et al 1996), and spinocerebellar ataxia type 6 (SCA6), the last identified SCA associated with a CAG expansion (Zhuchenko et al 1997).…”