X-chromosome inactivation patterns in females with Fabry disease examined by both ultra-deep RNA sequencing and methylation-dependent assay.
Female Fabry disease
HUMARA
Ultra-deep RNA sequencing
X-chromosome inactivation
Journal
Clinical and experimental nephrology
ISSN: 1437-7799
Titre abrégé: Clin Exp Nephrol
Pays: Japan
ID NLM: 9709923
Informations de publication
Date de publication:
Nov 2021
Nov 2021
Historique:
received:
06
12
2020
accepted:
09
06
2021
pubmed:
16
6
2021
medline:
27
1
2022
entrez:
15
6
2021
Statut:
ppublish
Résumé
Fabry disease is an X-linked inherited lysosomal storage disorder caused by mutations in the gene encoding α-galactosidase A. Males are usually severely affected, while females have a wide range of disease severity. This variability has been assumed to be derived from organ-dependent skewed X-chromosome inactivation (XCI) patterns in each female patient. Previous studies examined this correlation using the classical methylation-dependent method; however, conflicting results were obtained. This study was established to ascertain the existence of skewed XCI in nine females with heterozygous pathogenic variants in the GLA gene and its relationship to the phenotypes. We present five female patients from one family and four individual female patients with Fabry disease. In all cases, heterozygous pathogenic variants in the GLA gene were detected. The X-chromosome inactivation patterns in peripheral blood leukocytes and cells of urine sediment were determined by both classical methylation-dependent HUMARA assay and ultra-deep RNA sequencing. Fabry Stabilization Index was used to determine the clinical severity. Skewed XCI resulting in predominant inactivation of the normal allele was observed only in one individual case with low ⍺-galactosidase A activity. In the remaining cases, no skewing was observed, even in the case with the highest total severity score (99.2%). We conclude that skewed XCI could not explain the severity of female Fabry disease and is not the main factor in the onset of various clinical symptoms in females with Fabry disease.
Sections du résumé
BACKGROUND
BACKGROUND
Fabry disease is an X-linked inherited lysosomal storage disorder caused by mutations in the gene encoding α-galactosidase A. Males are usually severely affected, while females have a wide range of disease severity. This variability has been assumed to be derived from organ-dependent skewed X-chromosome inactivation (XCI) patterns in each female patient. Previous studies examined this correlation using the classical methylation-dependent method; however, conflicting results were obtained. This study was established to ascertain the existence of skewed XCI in nine females with heterozygous pathogenic variants in the GLA gene and its relationship to the phenotypes.
METHODS
METHODS
We present five female patients from one family and four individual female patients with Fabry disease. In all cases, heterozygous pathogenic variants in the GLA gene were detected. The X-chromosome inactivation patterns in peripheral blood leukocytes and cells of urine sediment were determined by both classical methylation-dependent HUMARA assay and ultra-deep RNA sequencing. Fabry Stabilization Index was used to determine the clinical severity.
RESULTS
RESULTS
Skewed XCI resulting in predominant inactivation of the normal allele was observed only in one individual case with low ⍺-galactosidase A activity. In the remaining cases, no skewing was observed, even in the case with the highest total severity score (99.2%).
CONCLUSION
CONCLUSIONS
We conclude that skewed XCI could not explain the severity of female Fabry disease and is not the main factor in the onset of various clinical symptoms in females with Fabry disease.
Identifiants
pubmed: 34128148
doi: 10.1007/s10157-021-02099-4
pii: 10.1007/s10157-021-02099-4
doi:
Substances chimiques
GLA protein, human
EC 3.2.1.22
alpha-Galactosidase
EC 3.2.1.22
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1224-1230Subventions
Organisme : Ministry of Education, Culture, Sports, Science and Technology
ID : 19K08726
Informations de copyright
© 2021. Japanese Society of Nephrology.
Références
Mehta A, et al. Fabry disease: a review of current management strategies. QJM. 2010;103(9):641–59.
doi: 10.1093/qjmed/hcq117
Desnick RJ. Fabry disease, an under-recognized multisystemic disorder:expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med. 2003;138:338–46.
doi: 10.7326/0003-4819-138-4-200302180-00014
Saito S, Ohno K, Sakuraba H. Fabry-database.org: database of the clinical phenotypes genotypes and mutant ⍺-galactosidase A sturctures in Fabry disease. J Hum Genet. 2011;56(6):467–8.
doi: 10.1038/jhg.2011.31
Fuller M, Meikle P, Hopwood J. Epidemiology of lysosomal storage diseases: an overview, in Fabry Disease: perspectives from 5 Years of FOS. In: Mehta A, Beck M, Sunder-Plassmann G, editors. Pharmagenesis. England: Oxford; 2006.
Sawada T, et al. Newborn screening for Fabry disease in the western region of Japan. Mol Genet Metab Rep. 2020;22:100562.
doi: 10.1016/j.ymgmr.2019.100562
Inoue T, et al. Newborn screening for Fabry disease in Japan: prevalence and genotypes of Fabry disease in a pilot study. J Hum Genet. 2013;58(8):548–52.
doi: 10.1038/jhg.2013.48
Spada M, et al. High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet. 2006;79(1):31–40.
doi: 10.1086/504601
Deegan P. Natural history of Fabry disease in females in the Fabry Outcome Survey. J Med Genet. 2006;43(4):347–52.
doi: 10.1136/jmg.2005.036327
Waldek S, et al. Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry. Genet Med. 2009;11:790–6.
doi: 10.1097/GIM.0b013e3181bb05bb
Whybra C, et al. The Main Severity Score Index: a new instrument for quantifying the Anderson–Fabry disease phenotype, and the response of patients to enzyme replacement therapy. Clin Genet. 2004;65:299–307.
doi: 10.1111/j.1399-0004.2004.00219.x
Elstein D, et al. X-inactivation in Fabry disease. Gene. 2012;505:266–8.
doi: 10.1016/j.gene.2012.06.013
Dobyns W, et al. Inheritance of most X-linked traits is not dominant or recessive, just X-linked. Am J Med Genet. 2004;129A:136–43.
doi: 10.1002/ajmg.a.30123
Morey C, Avner P. Genetics and epigenetics of the X chromosome. Ann N Y Acad Sci. 2010;1214:E18-33.
doi: 10.1111/j.1749-6632.2010.05943.x
Hossain MA, et al. Future clinical and biochemical predictions of Fabry disease in females by methylation studies of the GLA gene. Mol Genet Metab Rep. 2019;20:1–7.
Dobrovolny R. Relationship between X-inactivation and clinical in- volvement in Fabry heterozygotes. Eleven novel mutations in the alpha-galactosidase A gene in the Czech and Slovak population. J Mol Med (Berl). 2005;83(8):647–54.
doi: 10.1007/s00109-005-0656-2
Maier E. Disease manifestations and X inactivation in heterozygous females with Fabry disease. Acta Paediatr Suppl. 2006;95(451):30–8.
doi: 10.1080/08035320600618809
Allen RC, Zoghbi HY, Moseley A, Rosenblatt HF, Belmont J. Methylation of Hpall and Hhal sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet. 1992;51:1229–39.
pubmed: 1281384
pmcid: 1682906
Minamikawa S, et al. Development of ultra-deep targeted RNA sequencing for analyzing X-chromosome inactivation in female Dent disease. J Hum Genet. 2018;63:589–95.
doi: 10.1038/s10038-018-0415-1
Mignani R, et al. FAbry STabilization indEX (FASTEX): an innovative tool for the assessment of clinical stabilization in Fabry disease. Clin Kidney J. 2016;9(5):739–47.
doi: 10.1093/ckj/sfw082
Allen R, et al. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen receptor gene correlates With X Chromosome Inactivation. Am J Hum Genet. 1992;51(6):1229–39.
pubmed: 1281384
pmcid: 1682906
Lenders M, et al. Multicenter Female Fabry Study (MFFS)—clinical survey on current treatment of females with Fabry disease. Orphanet J Rare Dis. 2016;11:88.
doi: 10.1186/s13023-016-0473-4
Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:1–49.
doi: 10.1186/1750-1172-5-30
Eng CM, et al. Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis. 2007;30:184–92.
doi: 10.1007/s10545-007-0521-2
Echevarria L, et al. X-chromosome inactivation in female patients with Fabry disease. Clin Genet. 2016;89:44–54.
doi: 10.1111/cge.12613
Nowak A, et al. Plasma LysoGb3: a useful biomarker for the diagnosis and treatment of Fabry disease heterozygotes. Mol Genet Metab. 2017;120:57–61.
doi: 10.1016/j.ymgme.2016.10.006
Juchniewicz P, et al. Female Fabry disease patients and X-chromosome inactivation. Gene. 2018;641:259–64.
doi: 10.1016/j.gene.2017.10.064
Arcolino FO, et al. Human urine as a noninvasive source of kidney cells. Stem Cell Int. 2014;2015:1–7.
Botezatu I, et al. Genetic analysis of DNA excreted in urine: a new approach for detecting specific genomic DNA sequences from cells dying in an organism. Clin Chem. 2000;46:1078–84.
doi: 10.1093/clinchem/46.8.1078
Lichtenstein A, et al. Circulating nucleic acids and apoptosis. Ann N Y Acad Sci. 2001;945:239–49.
doi: 10.1111/j.1749-6632.2001.tb03892.x
Bittel D, et al. Comparison of X-chromosome inactivation patterns in multiple tissues from human females. J Med Genet. 2008;45:309–13.
doi: 10.1136/jmg.2007.055244
Sharp A, Robinson D, Jacobs P. Age- and tissue-specific variation of X chromosome inactivation ratios in normal women. Hum Genet. 2000;107:343–9.
doi: 10.1007/s004390000382
Gale R, et al. Tissue specificity of X-chromosome inactivation patterns. Blood. 1994;83:2899–905.
doi: 10.1182/blood.V83.10.2899.2899
Azofeifa J, Waldherr R, Cremer M. X-chromosome methylation ratiosas indicators of chromosomal activity: evidence of intraindividual diver-gencies among tissues of different embryonal origin. Hum Genet. 1996;97:330–3.
doi: 10.1007/BF02185765