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Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the α-galactosidase A gene in the Czech and Slovak population

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Abstract

We have identified 21 different α-galactosidase A gene (GLA) mutations in 22 unrelated Czech and Slovak families with Fabry disease. Eleven of these mutations were novel (point mutations D93N, A135V, D155H, G171R, Q280K, G360S, Q330X, splicing errors c.194ins14, c.801ins36 and deletions c.674_732del59, g.3405_6021del2617). Genotyping of family members for family-specific mutations revealed 55 heterozygotes that manifested clinical symptoms of different severity. To examine the contribution of X-inactivation skewing to disease manifestation in Fabry heterozygotes, we have adopted the Mainz severity scoring scheme and compared the score values with the X-inactivation status in 39 carriers in an age-dependent manner. The age-score trendline of Fabry females who had a predominantly inactivated X-chromosome bearing a wild-type GLA allele (10 of 38 females) was markedly steeper than in the rest of the cohort. One female carrier with an inactivated mutated allele had a low score value when compared to the other heterozygotes of the same age. These data suggest that X-inactivation is indeed a major factor determining the severity of clinical involvement in Fabry heterozygotes. There was a statistically significant difference between the severity score values of heterozygotes with random and non-random X-chromosome inactivation at the 5% level of significance. Further studies will show if the degree of the wildtype allele inactivation will be useful as a predictive marker of severity of phenotype in Fabry heterozygotes. Although the correlation between X-inactivation skewing and presentation of the disease in Fabry heterozygotes has previously been suggested in the literature, this report is among the first attempts to examine this relationship systematically.

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Acknowledgements

This work was supported by project grants IGA MZ CR NE 5770-3-99, VZ 111100003 and MSM 21620806. We thank Dr. Garman (Structural Biology Section, Laboratory of Immunogenetic Disease, National Institute of Allergy and Infectious Diseases, National Institute of Health) for giving us the coordinates of the human α-gal A structural model. We also thank Dr. Merta and Dr. Reiterová (First Department of Internal Medicine, General Teaching Hospital, Prague) for providing us with biological material from some of the Fabry families.

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Correspondence to Martin Hrebicek.

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Dobrovolny, R., Dvorakova, L., Ledvinova, J. et al. Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the α-galactosidase A gene in the Czech and Slovak population. J Mol Med 83, 647–654 (2005). https://doi.org/10.1007/s00109-005-0656-2

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