Future clinical and biochemical predictions of Fabry disease in females by methylation studies of the GLA gene
Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A (α-gal A). The clinical variability of the phenotypes of Fabry disease in females is still poorly understood. The degree of aberrant methylation of non-mutated alleles is thought to have significant e...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-09-01
|
| Series: | Molecular Genetics and Metabolism Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426919300795 |
| _version_ | 1818453545622437888 |
|---|---|
| author | Mohammad Arif Hossain Chen Wu Hiroko Yanagisawa Takashi Miyajima Keiko Akiyama Yoshikatsu Eto |
| author_facet | Mohammad Arif Hossain Chen Wu Hiroko Yanagisawa Takashi Miyajima Keiko Akiyama Yoshikatsu Eto |
| author_sort | Mohammad Arif Hossain |
| collection | DOAJ |
| description | Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A (α-gal A). The clinical variability of the phenotypes of Fabry disease in females is still poorly understood. The degree of aberrant methylation of non-mutated alleles is thought to have significant effects on X-chromosome inactivation (XCI). We previously reported that one heterozygous Fabry female showing classical phenotypes had complete methylation of the non-mutated allele of the GLA gene. In this report, we summarized 36 heterozygous females with a clinical severity score based on the FAbry STabilization indEX (FASTEX). We measured their α-gal A activity and plasma/ serum globotriaosylsphingosine (lyso-Gb3) accumulation and performed electron microscopy of skin biopsies. We analyzed the methylation-sensitive restriction enzyme sites throughout the GLA gene, including the 5’UTR, and found a single SacII site and multiple HhaI and HpaII sites aggregated in exon 1 and the 5’UTR. One HpaII sequence in exon 7 was also detected as a methylation-sensitive site. With methylation-sensitive restriction enzymes, methylated and non-methylated alleles could be separated, and the ratio of the methylation was quantified. We found a clear correlation between the severity of the phenotype and lyso-Gb3 accumulation for heterozygous Fabry disease in females. Methylation of the non-mutated allele was also proportionately correlated to the clinical severity score measured by FASTEX. Keywords: Heterozygous Fabry females, Fabry stabilization indEX, Methylation, X-chromosome inactivation |
| first_indexed | 2024-12-14T21:40:42Z |
| format | Article |
| id | doaj.art-4dd15a4d4f5b49698e0284a5233d12e1 |
| institution | Directory Open Access Journal |
| issn | 2214-4269 |
| language | English |
| last_indexed | 2024-12-14T21:40:42Z |
| publishDate | 2019-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj.art-4dd15a4d4f5b49698e0284a5233d12e12022-12-21T22:46:28ZengElsevierMolecular Genetics and Metabolism Reports2214-42692019-09-0120Future clinical and biochemical predictions of Fabry disease in females by methylation studies of the GLA geneMohammad Arif Hossain0Chen Wu1Hiroko Yanagisawa2Takashi Miyajima3Keiko Akiyama4Yoshikatsu Eto5Advanced Clinical Research Center, Institute of Neurological Disorders, Kawasaki, Kanagawa, Japan; Department of Gene Therapy, Institute for DNA Medicine, The Jikei University School of Medicine, Tokyo, Japan; Corresponding authors at: Advanced Clinical Research Center, Institute of Neurological Disorders, Shin-Yurigaoka General Hospital, Asao-Ku, Furusawa Tsuko 255, Kawasaki city, Kanagawa 215-0026, Japan.Advanced Clinical Research Center, Institute of Neurological Disorders, Kawasaki, Kanagawa, JapanAdvanced Clinical Research Center, Institute of Neurological Disorders, Kawasaki, Kanagawa, JapanAdvanced Clinical Research Center, Institute of Neurological Disorders, Kawasaki, Kanagawa, JapanAdvanced Clinical Research Center, Institute of Neurological Disorders, Kawasaki, Kanagawa, JapanAdvanced Clinical Research Center, Institute of Neurological Disorders, Kawasaki, Kanagawa, Japan; Department of Gene Therapy, Institute for DNA Medicine, The Jikei University School of Medicine, Tokyo, Japan; Corresponding authors at: Advanced Clinical Research Center, Institute of Neurological Disorders, Shin-Yurigaoka General Hospital, Asao-Ku, Furusawa Tsuko 255, Kawasaki city, Kanagawa 215-0026, Japan.Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A (α-gal A). The clinical variability of the phenotypes of Fabry disease in females is still poorly understood. The degree of aberrant methylation of non-mutated alleles is thought to have significant effects on X-chromosome inactivation (XCI). We previously reported that one heterozygous Fabry female showing classical phenotypes had complete methylation of the non-mutated allele of the GLA gene. In this report, we summarized 36 heterozygous females with a clinical severity score based on the FAbry STabilization indEX (FASTEX). We measured their α-gal A activity and plasma/ serum globotriaosylsphingosine (lyso-Gb3) accumulation and performed electron microscopy of skin biopsies. We analyzed the methylation-sensitive restriction enzyme sites throughout the GLA gene, including the 5’UTR, and found a single SacII site and multiple HhaI and HpaII sites aggregated in exon 1 and the 5’UTR. One HpaII sequence in exon 7 was also detected as a methylation-sensitive site. With methylation-sensitive restriction enzymes, methylated and non-methylated alleles could be separated, and the ratio of the methylation was quantified. We found a clear correlation between the severity of the phenotype and lyso-Gb3 accumulation for heterozygous Fabry disease in females. Methylation of the non-mutated allele was also proportionately correlated to the clinical severity score measured by FASTEX. Keywords: Heterozygous Fabry females, Fabry stabilization indEX, Methylation, X-chromosome inactivationhttp://www.sciencedirect.com/science/article/pii/S2214426919300795 |
| spellingShingle | Mohammad Arif Hossain Chen Wu Hiroko Yanagisawa Takashi Miyajima Keiko Akiyama Yoshikatsu Eto Future clinical and biochemical predictions of Fabry disease in females by methylation studies of the GLA gene Molecular Genetics and Metabolism Reports |
| title | Future clinical and biochemical predictions of Fabry disease in females by methylation studies of the GLA gene |
| title_full | Future clinical and biochemical predictions of Fabry disease in females by methylation studies of the GLA gene |
| title_fullStr | Future clinical and biochemical predictions of Fabry disease in females by methylation studies of the GLA gene |
| title_full_unstemmed | Future clinical and biochemical predictions of Fabry disease in females by methylation studies of the GLA gene |
| title_short | Future clinical and biochemical predictions of Fabry disease in females by methylation studies of the GLA gene |
| title_sort | future clinical and biochemical predictions of fabry disease in females by methylation studies of the gla gene |
| url | http://www.sciencedirect.com/science/article/pii/S2214426919300795 |
| work_keys_str_mv | AT mohammadarifhossain futureclinicalandbiochemicalpredictionsoffabrydiseaseinfemalesbymethylationstudiesoftheglagene AT chenwu futureclinicalandbiochemicalpredictionsoffabrydiseaseinfemalesbymethylationstudiesoftheglagene AT hirokoyanagisawa futureclinicalandbiochemicalpredictionsoffabrydiseaseinfemalesbymethylationstudiesoftheglagene AT takashimiyajima futureclinicalandbiochemicalpredictionsoffabrydiseaseinfemalesbymethylationstudiesoftheglagene AT keikoakiyama futureclinicalandbiochemicalpredictionsoffabrydiseaseinfemalesbymethylationstudiesoftheglagene AT yoshikatsueto futureclinicalandbiochemicalpredictionsoffabrydiseaseinfemalesbymethylationstudiesoftheglagene |