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Genetics101981; Cantu et al, 1985; Sutherland et al, 1985),and cell density (Cantu et al, 1985; Krawczun et al,1986). (The 1991 guidelines recommendedstandardisation of the number and type ofinduction systems used and the number of cellscounted.) Third, the assay is affected by factorsother than the presence of fragile X syndrome.Oral intake of folic acid in the diet might decreasethe frequency of FRAXA expression (Brown et al,1984; Gustavson et al, 1985). Also, an inverserelationship between age and cytogenetic expressionhas been observed in females (Rousseauet al, 1991b), although this relationship has notbeen demonstrated in males (Brøndum Nielsen& Tommerup, 1984).Molecular geneticsClassically, genetic diseases (e.g. cystic fibrosis,Tay–Sachs disease, sickle cell anaemia) are eitherinherited in a recessive or dominant Mendelianform or the result of a new mutation. Fragile Xsyndrome does not behave like this, and is nowknown to be an example of a different type ofgenetic disease caused by a ‘dynamic’ mutationwhich is heritably unstable (Richard & Sutherland,1992). Here, an initial change in the DNA sequenceincreases the tendency to further mutationwithin subsequent generations. Fragile X syndromeis the result of a dynamic mutation in a gene at theFRAXA locus that is referred to as fragile X mentalretardation-1 (FMR-1) (Kremer et al, 1991; Verkerket al, 1991; Fu et al, 1991). Dynamic mutations arenow known to be also responsible for spinobulbarmuscular atrophy (Kennedy’s disease) (La Spadaet al, 1991), myotonic dystrophy (Brook et al, 1992;Mahadevan et al, 1992; Fu et al, 1992), Huntington’sdisease (Huntington’s Disease CollaborativeResearch Group, 1993), spinocerebellar ataxia type1 (Orr et al, 1993), dentatorubral pallidoluysianatrophy (Koide et al, 1994; Nagafuchi et al, 1994)and the mental retardation associated with FRAXE(Knight et al, 1993).FMR-1 geneThis gene spans 39 kb containing 17 exons(Eichler et al, 1993). The FRAXA site, located inthe untranslated region of the first exon (Verkerket al, 1991; Yu et al, 1992; Caskey et al, 1992; Ashleyet al, 1993b), is characterised by the presenceof an array comprising a repeat sequence of thetrinucleotide CGG interspersed with singleadenine–guanine–guanine (AGG) repeats alongits length (Verkerk et al, 1991; Fu et al, 1991;Kremer et al, 1991). A CpG island, thought tobe the gene promoter, is located approximately250 bp distal of the CGG repeat (Verkerk et al,1991; Bell et al, 1991; Oberlé et al, 1991). FMR-1normally transcribes a cytoplasmic protein product(Verheij et al, 1993), FMRP, which is ubiquitouslyexpressed at low levels and at a higher levels inthe testes and brain (Devys et al, 1993; Bachneret al, 1993; Hinds et al, 1993; Verheij et al, 1995).Although the exact function of the gene productis not known, protein characterisation has shownthat it contains sequence motifs characteristicof ribosomal RNA-binding proteins (Siomi et al,1993; Ashley et al, 1993a; Feng et al, 1995a; Khandjianet al, 1996). The absence of this product isbelieved to be responsible for the clinical phenotypeof fragile X syndrome (Gedeon et al, 1992;Wöhrle et al, 1992a; Verheij et al, 1993; Meijeret al, 1994).The array is polymorphic in respect of the numberof CGG repeats it includes, as well as the numberand position of the interspersed AGGs (Fu et al,1991; Snow et al, 1993; Eichler et al, 1994; Hirstet al, 1994; Kunst & Warren, 1994; Snow et al, 1994).The different alleles are usually referred to by the‘repeat size’ of the array, that is, the total numberof both CGG and AGG repeats. Size is the principaldeterminant of whether an allele is regarded asnormal or mutated.Normal allelesDistribution of repeat sizesIn the unaffected population the most commonrepeat size is 30. The lowest reported size is 5 andthe upper limit of normal is generally taken to be54 (Fu et al, 1991) although some studies use 52 asthe upper limit. These alleles are inherited stably,although small changes in size can occur betweengenerations. The frequency distribution of repeatsizes in the unaffected population, compiled fromfive studies, is shown in Figure 1 (Snow et al, 1993;Dawson et al, 1995; Eichler et al, 1995a; Brown et al,1996; Kunst et al, 1996), and includes a total of6052 normal X chromosomes.Female allelesIn a proportion of females with normal allelesthere is a difference in the size of the repeatsequences on the two X chromosomes; suchfemales are referred to as heterozygous normal.The remaining females with equal repeat sizesare referred to as homozygous normal. Table 2,compiled from five studies, shows that in a totalof 1518 normal females, 29% were homozygous.
Health Technology Assessment 1997; Vol. 1: No. 415 25 35 45 55Repeat sizeFIGURE 1 Population distribution of the normal allele sizeTABLE 2 Proportion of normal females who are homozygousfor the repeat size: results from five studiesStudy Number of Homozygousindividuals (%)USA, NY 206 44 (21)Brown et al, 1993Japan 227 66 (29)Arinami et al, 1993USA, Rochester 197 35 (18)Snow et al, 1993Canada 735 242 (33)Dawson et al, 1995UK, Leeds 153 51 (33)(Unpublished data)All 1518 438 (29)Mutated allelesIn affected families there are mutations in theFMR-1 gene which lead to hereditary instabilityand which, ultimately, cause the disorder (Bellet al, 1991; Kremer et al, 1991; Oberlé et al, 1991;Verkerk et al, 1991; Yu et al, 1991). The mutationsare characterised by a substantial increase (or‘expansion’) in repeat size compared to normal;two principal classes of mutation have beendefined, the PM and the FM, according to thesize. FMs are associated with clinical fragile Xsyndrome; PMs are not but carry a high risk ofexpansion between mother and offspring (seeFigure 2).Full mutationIf the repeat size exceeds 200 there is said tobe an FM. This generally coincides with abnormalmethylation of the nearby CpG island (Verkerket al, 1991; Bell et al, 1991) and is thought to bepartly responsible for down-regulation of theFMR-1 gene (Pieretti et al, 1991; Sutcliffe et al,1992); in individuals with an FM and methylation,the FMR-1 mRNA cannot be detected.Pre-mutationThe PM repeat size ranges from approximately55 to 199, although there is a grey zone betweennormal and PM alleles (see page 13). In cellswith a PM, the FRAXA site is rarely cytogeneticallyexpressed and there is no methylation of theFMR-1 gene; several studies have observed bothFMR-1 mRNA and FMRP in these cells (Pierettiet al, 1991; Devys et al, 1993; Siomi et al, 1993;Feng et al, 1995a).MosaicsThere are various types of mosaicism commonlyfound in individuals with an FM genotype. First,there is ‘size’ mosaicism, in which those with anFM also have PM cell lines. The results from sevenstudies which included a total of 604 males and11
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