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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.

SUBMITTER: Redonnet-Vernhet I

PROVIDER: S-EPMC1050704 | biostudies-other | 1996 Aug

REPOSITORIES: biostudies-other

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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.

Redonnet-Vernhet I I Ploos van Amstel J K JK Jansen R P RP Wevers R A RA Salvayre R R Levade T T

Journal of medical genetics 19960801 8

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 h ...[more]

PMID: 8863162

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Project description:PurposeMonozygotic (MZ) twin pairs discordant for disease allow careful examination of environmental factors whilst controlling for genetic variation. The purpose of this study was to examine differences in environmental risk factors in MZ twins discordant for myopia.MethodsSixty four MZ twin pairs discordant for refractive error were interviewed. Discordant twins were selected from 1326 MZ twin pairs from the TwinsUK adult twin registry with non-cycloplegic autorefraction. Discordancy was defined as ≥ 2 Dioptres (D) difference in spherical equivalent (SphE) and discordant for class of refractive error. In a 35-item telephone questionnaire twins were separately asked (and scored) about the risk factors urban/rural residence, occupational status and highest educational level. They responded with more (1), less (-1) or the same (0) as their twin on time spent outside, playing outdoor sport, and on close work aged <16 and 16-25 years. The lower SphE twin's score was subtracted from the higher SphE twin's score, and mean values of the difference calculated for each variable.ResultsSixty four twin pairs were included (mean age 56, range 30-79 years; mean difference in refraction 3.35 D, S.D. 1.55 D, median difference 2.78 D). Within discordant MZ twin pairs, the more myopic twin was associated with having a higher occupational status (mean score between 16 and 25 years -0.11; 95% CI -0.19 to -0.04; mean score aged >25 years -0.23, 95% CI -0.28 to -0.17), being resident in urban area (mean score -0.26; 95% CI -0.33 to -0.18) and performing more close work (mean score <16 years -0.11; 95% CI -0.18 to -0.05; mean score aged 16-25 years -0.17, 95% CI -0.24 to -0.10) than their twin. The twins who spent more time outdoors (mean score <16 years 0.09; 95% CI 0.03-0.15; mean score aged 16-25 years 0.28, 95% CI 0.15-0.41) or performed more outdoors sports (mean score <16 years 0.13; 95% CI 0.04-0.21; mean score aged 16-25 years 0.23, 95% CI 0.10-0.36) were less likely to be myopic than their twin.ConclusionsThis study has confirmed known environmental risk factors for myopia. These data will allow selection of discordant twins for epigenetic analysis to advance knowledge of mechanisms of refractive error development.

Dataset Information

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.

Publications

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.

Similar Datasets

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