Clinical course, mutations and its functional characteristics of infantile-onset Pompe disease in Thailand
| Autor: | Duangrurdee Wattanasirichaigoon, Kitiwan Rojnueangnit, Suthipong Pangkanon, Thipwimol Tim-Aroon, Saisuda Noojaroen, Ratana Charoenwattanasatien, Voraratt Champattanachai, Jisnuson Svasti, Lukana Ngiwsara, Phannee Sawangareetrakul, James R. Ketudat-Cairns, Arthaporn Khongkraparn, Chulaluck Kuptanon |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Models Molecular 0301 basic medicine 030105 genetics & heredity medicine.disease_cause Exon Sequence Analysis Protein Chlorocebus aethiops Glycogen storage disease type II Coding region GAA Pathology Molecular Genetics (clinical) Genetics education.field_of_study Mutation Pompe disease Thailand COS Cells Acid alpha-glucosidase Female Research Article lcsh:Internal medicine lcsh:QH426-470 Population Biology 03 medical and health sciences Asian People Lysosomal strorage disorder medicine Animals Humans Enzyme Replacement Therapy Genetic Predisposition to Disease Allele education lcsh:RC31-1245 Gene Acid alpha glucosidase Alleles Base Sequence Infant alpha-Glucosidases Cardiomyopathy Hypertrophic medicine.disease lcsh:Genetics 030104 developmental biology |
| Zdroj: | BMC Medical Genetics, Vol 20, Iss 1, Pp 1-11 (2019) BMC Medical Genetics |
| ISSN: | 1471-2350 |
| DOI: | 10.1186/s12881-019-0878-8 |
| Popis: | BackgroundPompe disease is a lysosomal storage disorder caused by the deficiency of acid alpha-glucosidase (EC. 3.2.1.20) due to mutations in humanGAAgene. The objective of the present study was to examine clinical and molecular characteristics of infantile-onset Pompe disease (IOPD) in Thailand.MethodsTwelve patients with infantile-onset Pompe disease (IOPD) including 10 Thai and two other Asian ethnicities were enrolled. To examine the molecular characteristics of Pompe patients,GAAgene was analyzed by PCR amplification and direct Sanger-sequencing of 20 exons coding region. The novel mutations were transiently transfected in COS-7 cells for functional verification. The severity of the mutation was rated by study of the GAA enzyme activity detected in transfected cells and culture media, as well as the quantity and quality of the proper sized GAA protein demonstrated by western blot analysis. The GAA three dimensional structures were visualized by PyMol software tool.ResultsAll patients had hypertrophic cardiomyopathy, generalized muscle weakness, and undetectable or G (p.Tyr292X), c.1226insG (p.Asp409GlyfsX95), c.1538G > A (p.Asp513Gly), c.1895 T > G (p.Leu632Arg), and a previously reported rare allele of unknown significance: c.781G > A (p.Ala261Thr) were identified. The rating system ranked p.Tyr292X, p. Asp513Gly and p. Leu632Arg as class “B” and p. Ala261Thr as class “D” or “E”. These novel mutations were located in the N-terminal beta-sheet domain and the catalytic domain.ConclusionsThe present study provides useful information on the mutations ofGAAgene in the underrepresented population of Asia which are more diverse than previously described and showing the hotspots in exons 14 and 5, accounting for 62% of mutant alleles. Almost all mutations identified are in class A/B. These data can benefit rapid molecular diagnosis of IOPD and severity rating of the mutations can serve as a partial substitute for cross reactive immunological material (CRIM) study. |
| Databáze: | OpenAIRE |
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