title: Uneven X inactivation in a female monozygotic twin pair with Fabry disease and discordant expression of a novel mutation in the alpha-galactosidase A gene.
abstract: We describe two female monozygotic (MZ) twins heterozygous for Fabry disease, an X linked disorder resulting from the deficient activity of alpha-galactosidase A. While one of the twins was clinically affected, the other was asymptomatic. Enzymatic assay of alpha-galactosidase in blood leucocytes, skin fibroblasts, Epstein-Barr virus transformed lymphoid cell lines, and hair follicles of the twins and their parents confirmed the heterozygous status of the twins and indicated that Fabry disease had occurred as a result of a de novo mutation. The son of the unaffected twin sister was shown to be hemizygous. Molecular analysis of the alpha-galactosidase A gene permitted the identification of an as yet undescribed point mutation at position 10182 of exon 5 which causes an Asp to Asn substitution at codon 231. Single strand conformation polymorphism (SSCP) analysis again showed the heterozygous status of the twins and a normal pattern in their parents. The basis for the discordant expression of this d novo mutation in the twins was investigated by studying their X inactivation status. Analysis of the inactive X specific methylation at the androgen receptor gene showed unbalanced inactivation in the twins' fibroblasts and in opposite directions. While the maternally derived X chromosome was preferentially active in the asymptomatic twin, the paternal X chromosome was active in the other, affected twin and was found in her hemizygotic nephew. These data suggest that the paternal X chromosome carries the de novo alpha-galactosidase A mutation and that uneven X inactivation is the underlying mechanism for disease expression in this novel female MZ twin pair. This is the first documented case of female twins discordant for Fabry disease.
authors.affiliation: CJF INSERM 9206, Laboratoire de Biochimie Médicale, Maladies Métaboliques, Institut Louis Bugnard, CHU Rangueil, Toulouse, France.
authors.forename: I
authors.initials: I
authors.lastname: Redonnet-Vernhet
authors.forename: J K
authors.initials: JK
authors.lastname: Ploos van Amstel
authors.forename: R P
authors.initials: RP
authors.lastname: Jansen
authors.forename: R A
authors.initials: RA
authors.lastname: Wevers
authors.forename: R
authors.initials: R
authors.lastname: Salvayre
authors.forename: T
authors.initials: T
authors.lastname: Levade
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D019175:DNA Methylation; D004303:Dosage Compensation, Genetic; D000795:Fabry Disease / Q000201:enzymology / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D005796:Genes / Q000235:genetics; D018859:Hair Follicle; D006579:Heterozygote; D006801:Humans; D007962:Leukocytes / Q000201:enzymology; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D011944:Receptors, Androgen / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics*; D000519:alpha-Galactosidase / Q000235:genetics* / Q000378:metabolism
chemical_list: D011944:Receptors, Androgen; D000519:alpha-Galactosidase