de Diego Otero, MY (Yolanda)

Olmer, R

Oostra, Ben

Willemsen, Rob

English

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doi:10.1136/jmg.37.8.603  2000;37;603-604 J. Med. Genet.  Rob Willemsen, Renske Olmer, Yolanda De Diego Otero and Ben A Oostra    mutation, but with a different phenotypeTwin sisters, monozygotic with the fragile X http://jmg.bmj.com/cgi/content/full/37/8/603Updated information and services can be found at:  These include: References http://jmg.bmj.com/cgi/content/full/37/8/603#otherarticles2 online articles that cite this article can be accessed at:    http://jmg.bmj.com/cgi/content/full/37/8/603#BIBLThis article cites 16 articles, 3 of which can be accessed free at: Rapid responses http://jmg.bmj.com/cgi/eletter-submit/37/8/603You can respond to this article at:    http://jmg.bmj.com/cgi/content/full/37/8/603#responsesOne rapid response has been posted to this article, which you can access for free at: serviceEmail alertingtop right corner of the article Receive free email alerts when new articles cite this article - sign up in the box at theTopic collections (3948 articles) Genetics   Articles on similar topics can be found in the following collections  Notes    http://www.bmjjournals.com/cgi/reprintformTo order reprints of this article go to:  http://www.bmjjournals.com/subscriptions/ go to: Journal of Medical GeneticsTo subscribe to  on 29 November 2006 jmg.bmj.comDownloaded from Twin sisters, monozygotic with the fragile Xmutation, but with a diVerent phenotypeRob Willemsen, Renske Olmer, Yolanda De Diego Otero, Ben A OostraAbstractThe absence of the fragile X mental retar-dation protein (FMRP) results in fragile Xsyndrome. All males with a full mutationin the FMR1 gene and an inactive FMR1gene are mentally retarded while 60% ofthe females with a full mutation areaVected. Here we describe monozygotictwin sisters who both have a full mutationin their FMR1 gene, one of whom isnormal while the other is aVected. Usingmolecular and protein studies it wasshown that owing to preferential X inacti-vation in the aVected female a minority ofthe cells expressed the normal FMR1gene, while in her sister most cells ex-pressed the normal FMR1 gene. Thisshows that X inactivation took place in thefemale twins after separation of the em-bryos and that for a normal phenotypeFMR1 expression is necessary in themajority of cells.(J Med Genet 2000;37:603–604)Keywords: fragile X syndrome; mental retardation;monozygotic twins; LyonisationFragile X syndrome is the most common formof X linked inherited mental retardation inhumans with a prevalence of 1:4000 males and1:6000 females.1 The basic genetic defect is anincrease in length of a stretch of CGG tripletrepeats (>200 repeats, full mutation) withinthe FMR1 gene.2 The large number of CGGrepeats leads to silencing of the FMR1 geneand consequently the absence of the encodedFMR1 protein (FMRP).3 4 The absence ofFMRP in the brain is responsible for theobserved mental retardation. Males carryingthe full mutation are always aVected, whereasfemales carrying a full mutation show mentalimpairment in only approximately 60% ofcases. Females carrying a full mutation arecharacterised by cells with and without FMRPexpression, which can be explained by inactiva-tion of the X chromosome (Lyonisation).Thus, in cells without FMRP expression thenormal FMR1 allele is inactivated, whereas incells with FMRP expression the mutant FMR1allele is inactivated. It has been suggested thatan insuYcient number of FMRP expressingneurones in the brain in aVected females causesthe mental retardation as a result of theproportion of mutant FMR1 alleles on theactive X chromosome.Monozygous twins are genetically identicaland concordance for cognitive function be-tween monozygous twins carrying a full muta-tion would be expected. At least three cases oflive born male monozygotic twins with thefragile X syndrome have been published andthree pairs of brothers were concordant for themental retardation.5–7 One of the male twinshad a diVerent size of the full mutation.6 Noinformation about the time of twinning wasavailable. Of the four sister pairs withretardation,5 6 8 9 one pair was concordant formental retardation.5 Of the other three, onlyone sister was mentally retarded. Two of thethree pairs had significant diVerences in Xinactivation pattern showing that in the normalgirl the X chromosome with the full mutationwas preferentially inactivated. For an overviewof twin studies in fragile X syndrome see Hel-derman et al.10Here we describe the unexpected observa-tion of diVerent phenotypes in monozygotictwin sisters with the full mutation. One sister isaVected and is living in an institute for thementally handicapped without having typicalfeatures of fragile X syndrome, but this is oftenseen in aVected females. The other sister isintellectually normal and has finished second-ary school. Unfortunately their IQ values arenot available.Molecular studies on DNA isolated fromblood showed that both had a full mutation (fig1), but in the normal sister in almost all bloodcells the normal X chromosome was active (“Nactive”), while in the aVected sister the normalX chromosome is inactive in approximately50% of her blood cells (“N active + Ninactive”). However, it should be noted that inDNA studies performed so far, only a weakcorrelation has been found between the Xinactivation pattern and cognitive function.11–15However, this weak correlation is not strongenough to be a prognostic indicator.Recently, we described a non-invasive anti-body test for fragile X syndrome using hair rootanalysis.16 This test oVers an aVordable andalternative tool for identifying fragile X pa-tients. We have hypothesised that this new testmight be of value for predicting the mentalcapacities of females carrying a full mutationbecause hair roots originate, like brain tissue,from the ectoderm during embryonic develop-ment.The aVected sister shows FMRP expressionin 35% of 20 hair roots, whereas her mentallynormal sister shows it in 79% of 18 hair roots(fig 1). In controls (>130 persons), FMRPexpression in hair roots was found to bebetween 77 and 100%, whereas aVectedfemales carrying a full mutation showed FMRPexpression in only some of their hair roots(<55%).16J Med Genet 2000;37:603–604 603CBG Department ofClinical Genetics,Erasmus University,PO Box 1738, 3000 DRRotterdam, TheNetherlandsR WillemsenR OlmerY D D OteroB A OostraCorrespondence to:Dr Oostra,oostra@kgen.fgg.eur.nlRevised version received30 March 2000Accepted for publication 14April 2000www.jmedgenet.com on 29 November 2006 jmg.bmj.comDownloaded from In conclusion, we were able to show in thiscase a correlation between FMRP expressionin hair roots and cognitive function in thesemonozygotic twin sisters, who are discordantfor the fragile X syndrome. We can explain thediscordance of mental capacity between thetwin sisters by the fact that the number ofFMRP expressing neurones in the brain of theaVected sister is insuYcient to prevent mentalretardation. In contrast, her normal sister has asuYcient number of FMRP expressing neu-rones in the brain to develop normal cognitivefunction in adult life. The results look promis-ing for the development of a diagnostic test topredict the mental status of females carryingthe full mutation. In addition, these results alsoshow that the Lyonisation and inactivation pat-terning took place in the female twins afterseparation of the embryos.1 Turner G, Webb T, Wake S, Robinson H. The prevalence ofthe fragile X syndrome. Am J Med Genet 1996;64:196-7.2 Verkerk AJ, Pieretti M, SutcliVe JS, Fu YH, Kuhl DP,Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP,Eussen BE, Van Ommen GJB, Blonden LAJ, Riggins GJ,Chastain JL, Kunst CB, Galjaard H, Caskey CT, NelsonDL, Oostra BA, Warren ST. Identification of a gene(FMR-1) containing a CGG repeat coincident with abreakpoint cluster region exhibiting length variation infragile X syndrome. Cell 1991;65:905-14.3 SutcliVe JS, Nelson DL, Zhang F, Pieretti M, Caskey CT,Saxe D, Warren ST. DNA methylation represses FMR-1transcription in fragile X syndrome. Hum Mol Genet 1992;1:397-400.4 Verheij C, Bakker CE, de GraaV E, Keulemans J, WillemsenR, Verkerk AJ, Galjaard H, Reuser AJ, Hoogeveen AT, Oos-tra BA. Characterization and localization of the FMR-1gene product associated with fragile X syndrome. Nature1993;363:722-4.5 Devys D, Biancalana V, Rousseau F, Boue J, Mandel JL,Oberle I. Analysis of full fragile X mutations in fetal tissuesand monozygotic twins indicate that abnormal methylationand somatic heterogeneity are established early in develop-ment. Am J Med Genet 1992;43:208-16.6 Kruyer H, Mila M, Glover G, Carbonell P, Ballesta F,Estivill X. Fragile X syndrome and the (CGG)n mutation -two families with discordant Mz twins. Am J Hum Genet1994;54:437-42.7 Antinolo G, Borrego S, Cabeza JC, Sanchez R, Sanchez J,Sanchez B. Reverse mutation in fragile X syndrome. Am JHum Genet 1996;58:237-9.8 Malmgren H, Steen-Bondeson ML, Gustavson KH, See-manova E, Holmgren G, Oberle I, Mandel JL, PetterssonU, Dahl N. Methylation and mutation patterns in the frag-ile X syndrome. Am J Med Genet 1992;43:268-78.9 Reiss AL, Abrams MT, Greenlaw R, Freund L, DencklaMB. Neurodevelopmental eVects of the FMR-1 full muta-tion in humans. Nat Med 1995;1:159-67.10 Helderman-van den Enden AT, Maaswinkel-Mooij PD,Hoogendoorn E, Willemsen R, Maat-Kievit JA, LosekootM, Oostra BA. Monozygotic twin brothers with the fragileX syndrome: diVerent CGG repeats and diVerent mentalcapacities. J Med Genet 1999;36:253-7.11 Taylor AK, Safanda JF, Fall MZ, Quince C, Lang KA, HullCE, Carpenter I, Staley LW, Hagerman RJ. Molecular pre-dictors of cognitive involvement in female carriers of fragileX syndrome. JAMA 1994;271:507-14.12 Abrams MT, Reiss AL, Freund LS, Baumgardner TL,Chase GA, Denckla MB. Molecular-neurobehavioral asso-ciations in females with the fragile X full mutation. Am JMed Genet 1994;51:317-27.13 De Vries LBA, Wiegers AM, Smits APT, Mohkamsing S,Duivenvoorden HJ, Fryns JP, Curfs LMG, Halley DJJ,Oostra BA, W. VdOAM, Niermeijer MF. Mental status offemales with a FMR1 gene full mutation. Am J Hum Genet1996;58:1025-32.14 Riddle JE, Cheema A, Sobesky WE, Gardner SC, TaylorAK, Pennington BF, Hagerman RJ. Phenotypic involve-ment in females with the FMR1 gene mutation. Am J MentRetard 1998;102:590-601.15 Tassone F, Hagerman RJ, Ikle DN, Dyer PN, Lampe M,Willemsen R, Oostra BA, Taylor AK. FMRP expression asa potential prognostic indicator in fragile X syndrome. AmJ Med Genet 1999;84:250-61.16 Willemsen R, Anar B, de Diego Otero Y, de Vries BB,Hilhorst-Hofstee Y, Smits A, van Looveren E, Willems PJ,Galjaard H, Oostra BA. Noninvasive test for fragile X syn-drome, using hair root analysis. Am J Hum Genet 1999;65:98-103.Figure 1 (Upper panel) Family pedigree showingmonozygotic twin sisters with fragile X mutation and theirphenotype. (Middle panel) Analysis of the FMR1 genewith probe pP2 of HindIII and EagI digested DNA isolatedfrom blood; N active: normal allele on active Xchromosome; N inactive: normal allele on inactive Xchromosome; Full: inactive allele with full mutation. (Lowerpanel) Percentage of hair roots expressing FMRP using anindirect alkaline phosphatase immunolabelling technique.16604 Willemsen, Olmer, Otero, et alwww.jmedgenet.com on 29 November 2006 jmg.bmj.comDownloaded from 

Twin sisters, monozygotic with the fragile X mutation, but with a different phenotype

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Twin sisters, monozygotic with the fragile X mutation, but with a different phenotype

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