Precise mapping of the fragile siteFRA12Aon chromosome 12q13.1

Abstract

AbstractIntroduction A causative relationship has been reported between fragile site expression and disease forFRA12A, a rare, folate‐sensitive fragile site on chromosome 12q13.1.FRA12Aexpression has been described in a number of patients with mental retardation, sometimes in combination with clinical abnormalities. In correspondence to the molecular mechanism of previously cloned, rare, fragile sites, it may be expected thatFRA12Ais caused by repeat expansion, affecting the expression of genes in the region. To identify the repeat and the associated gene, this paper reports the precise mapping ofFRA12Aon chromosome 12q12–13.Methods Fluorescencein situhybridization (FISH) techniques were used to mapYACandPACclones in the neighbourhood ofFRA12A.PACDNA pools andPACfilters were screened to find additionalPACclones spanning the candidate region. Markers in the region were obtained via web searches and used to construct bothPACandYACcontigs.Results and Discussion A singleYACclone that overspans the fragile site was identified and a completeYACandPACcontig for theFRA12Aregion was constructed. The region contains several candidate genes, including a calcium ion channel (CACNLB3), a GTP‐binding factor (ARF3), a gene involved in brain development (INT1) and two other genes involved in developmental processes (WNT10BandALR). TheFXR1gene, a homologue of theFMR1gene, that is associated with fragile X syndrome and that maps to chromosome 12q12–13, was ruled out as a possible candidate gene for theFRA12Asite.