Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation
Abstract Background Gaucher disease is a rare pan-ethnic, lysosomal storage disorder resulting due to beta-Glucosidase (GBA1) gene defect. This leads to the glucocerebrosidase enzyme deficiency and an increased accumulation of undegraded glycolipid glucocerebroside inside the cells’ lysosomes. To da...
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2019-02-01
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Series: | BMC Medical Genetics |
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Online Access: | http://link.springer.com/article/10.1186/s12881-019-0759-1 |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jayesh Sheth Riddhi Bhavsar Mehul Mistri Dhairya Pancholi Ashish Bavdekar Ashwin Dalal Prajnya Ranganath Katta M Girisha Anju Shukla Shubha Phadke Ratna Puri Inusha Panigrahi Anupriya Kaur Mamta Muranjan Manisha Goyal Radha Ramadevi Raju Shah Sheela Nampoothiri Sumita Danda Chaitanya Datar Seema Kapoor Seema Bhatwadekar Frenny Sheth |
spellingShingle |
Jayesh Sheth Riddhi Bhavsar Mehul Mistri Dhairya Pancholi Ashish Bavdekar Ashwin Dalal Prajnya Ranganath Katta M Girisha Anju Shukla Shubha Phadke Ratna Puri Inusha Panigrahi Anupriya Kaur Mamta Muranjan Manisha Goyal Radha Ramadevi Raju Shah Sheela Nampoothiri Sumita Danda Chaitanya Datar Seema Kapoor Seema Bhatwadekar Frenny Sheth Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation BMC Medical Genetics Gaucher disease β-Glucosidase Chitotriosidase GBA1 gene Glucocerebrosidase Indian population |
author_facet |
Jayesh Sheth Riddhi Bhavsar Mehul Mistri Dhairya Pancholi Ashish Bavdekar Ashwin Dalal Prajnya Ranganath Katta M Girisha Anju Shukla Shubha Phadke Ratna Puri Inusha Panigrahi Anupriya Kaur Mamta Muranjan Manisha Goyal Radha Ramadevi Raju Shah Sheela Nampoothiri Sumita Danda Chaitanya Datar Seema Kapoor Seema Bhatwadekar Frenny Sheth |
author_sort |
Jayesh Sheth |
title |
Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation |
title_short |
Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation |
title_full |
Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation |
title_fullStr |
Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation |
title_full_unstemmed |
Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation |
title_sort |
gaucher disease: single gene molecular characterization of one-hundred indian patients reveals novel variants and the most prevalent mutation |
publisher |
BMC |
series |
BMC Medical Genetics |
issn |
1471-2350 |
publishDate |
2019-02-01 |
description |
Abstract Background Gaucher disease is a rare pan-ethnic, lysosomal storage disorder resulting due to beta-Glucosidase (GBA1) gene defect. This leads to the glucocerebrosidase enzyme deficiency and an increased accumulation of undegraded glycolipid glucocerebroside inside the cells’ lysosomes. To date, nearly 460 mutations have been described in the GBA1 gene. With the aim to determine mutations spectrum and molecular pathology of Gaucher disease in India, the present study investigated one hundred unrelated patients (age range: 1 day to 31 years) having splenomegaly, with or without hepatomegaly, cytopenia and bone abnormality in some of the patients. Methods The biochemical investigation for the plasma chitotriosidase enzyme activity and β-Glucosidase enzyme activity confirmed the Gaucher disease. The mutations were identified by screening the patients’ whole GBA gene coding region using bidirectional Sanger sequencing. Results The biochemical analysis revealed a significant reduction in the β-Glucosidase activity in all patients. Sanger sequencing established 71 patients with homozygous mutation and 22 patients with compound heterozygous mutation in GBA1 gene. Lack of identification of mutations in three patients suggests the possibility of either large deletion/duplication or deep intronic variations in the GBA1 gene. In four cases, where the proband died due to confirmed Gaucher disease, the parents were found to be a carrier. Overall, the study identified 33 mutations in 100 patients that also covers four missense mutations (p.Ser136Leu, p.Leu279Val, p.Gly383Asp, p.Gly399Arg) not previously reported in Gaucher disease patients. The mutation p.Leu483Pro was identified as the most commonly occurring Gaucher disease mutation in the study (62% patients). The second common mutations identified were p.Arg535Cys (7% patients) and RecNcil (7% patients). Another complex mutation Complex C was identified in a compound heterozygous status (3% patients). The homology modeling of the novel mutations suggested the destabilization of the GBA protein structure due to conformational changes. Conclusions The study reports four novel and 29 known mutations identified in the GBA1 gene in one-hundred Gaucher patients. The given study establishes p.Leu483Pro as the most prevalent mutation in the Indian patients with type 1 Gaucher disease that provide new insight into the molecular basis of Gaucher Disease in India. |
topic |
Gaucher disease β-Glucosidase Chitotriosidase GBA1 gene Glucocerebrosidase Indian population |
url |
http://link.springer.com/article/10.1186/s12881-019-0759-1 |
work_keys_str_mv |
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doaj-ed485e77876d41b99aa48a8d477af5c92021-04-02T14:49:12ZengBMCBMC Medical Genetics1471-23502019-02-0120111110.1186/s12881-019-0759-1Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutationJayesh Sheth0Riddhi Bhavsar1Mehul Mistri2Dhairya Pancholi3Ashish Bavdekar4Ashwin Dalal5Prajnya Ranganath6Katta M Girisha7Anju Shukla8Shubha Phadke9Ratna Puri10Inusha Panigrahi11Anupriya Kaur12Mamta Muranjan13Manisha Goyal14Radha Ramadevi15Raju Shah16Sheela Nampoothiri17Sumita Danda18Chaitanya Datar19Seema Kapoor20Seema Bhatwadekar21Frenny Sheth22FRIGE’s Institute of Human Genetics, FRIGE HouseFRIGE’s Institute of Human Genetics, FRIGE HouseFRIGE’s Institute of Human Genetics, FRIGE HouseFRIGE’s Institute of Human Genetics, FRIGE HouseKing Edward Memorial HospitalCentre for DNA Fingerprinting and DiagnosticsCentre for DNA Fingerprinting and DiagnosticsKasturba Medical CollegeKasturba Medical CollegeSanjay Gandhi Postgraduate Institute of Medical SciencesSir Ganga Ram HospitalThe Postgraduate Institute of Medical Education and ResearchThe Postgraduate Institute of Medical Education and ResearchKing Edward Memorial HospitalJ.K. Lone Mother and Child HospitalRainbow Children’s HospitalAnkur Institute of Child HealthAmrita Institute of Medical Sciences & Research CentreChristian Medical College & HospitalSahyadri Medical Genetics & Tissue Engineering FacilityMaulana Azad medical College and Associated Loknayak HospitalSterling HospitalFRIGE’s Institute of Human Genetics, FRIGE HouseAbstract Background Gaucher disease is a rare pan-ethnic, lysosomal storage disorder resulting due to beta-Glucosidase (GBA1) gene defect. This leads to the glucocerebrosidase enzyme deficiency and an increased accumulation of undegraded glycolipid glucocerebroside inside the cells’ lysosomes. To date, nearly 460 mutations have been described in the GBA1 gene. With the aim to determine mutations spectrum and molecular pathology of Gaucher disease in India, the present study investigated one hundred unrelated patients (age range: 1 day to 31 years) having splenomegaly, with or without hepatomegaly, cytopenia and bone abnormality in some of the patients. Methods The biochemical investigation for the plasma chitotriosidase enzyme activity and β-Glucosidase enzyme activity confirmed the Gaucher disease. The mutations were identified by screening the patients’ whole GBA gene coding region using bidirectional Sanger sequencing. Results The biochemical analysis revealed a significant reduction in the β-Glucosidase activity in all patients. Sanger sequencing established 71 patients with homozygous mutation and 22 patients with compound heterozygous mutation in GBA1 gene. Lack of identification of mutations in three patients suggests the possibility of either large deletion/duplication or deep intronic variations in the GBA1 gene. In four cases, where the proband died due to confirmed Gaucher disease, the parents were found to be a carrier. Overall, the study identified 33 mutations in 100 patients that also covers four missense mutations (p.Ser136Leu, p.Leu279Val, p.Gly383Asp, p.Gly399Arg) not previously reported in Gaucher disease patients. The mutation p.Leu483Pro was identified as the most commonly occurring Gaucher disease mutation in the study (62% patients). The second common mutations identified were p.Arg535Cys (7% patients) and RecNcil (7% patients). Another complex mutation Complex C was identified in a compound heterozygous status (3% patients). The homology modeling of the novel mutations suggested the destabilization of the GBA protein structure due to conformational changes. Conclusions The study reports four novel and 29 known mutations identified in the GBA1 gene in one-hundred Gaucher patients. The given study establishes p.Leu483Pro as the most prevalent mutation in the Indian patients with type 1 Gaucher disease that provide new insight into the molecular basis of Gaucher Disease in India.http://link.springer.com/article/10.1186/s12881-019-0759-1Gaucher diseaseβ-GlucosidaseChitotriosidaseGBA1 geneGlucocerebrosidaseIndian population |