Gaucher disease

Single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation 06 Biological Sciences 0601 Biochemistry and Cell Biology

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 & 3 others Seema Kapoor, Seema Bhatwadekar, Frenny Sheth

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number31
JournalBMC Medical Genetics
Volume20
Issue number1
DOIs
Publication statusPublished - 14-02-2019

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Gaucher Disease
Biological Science Disciplines
Biochemistry
Cell Biology
Mutation
Genes
Glucosidases
India
Enzymes
Glucosylceramides
beta-Glucosidase
Hepatomegaly
Molecular Pathology
Glycolipids
Splenomegaly
Missense Mutation
Lysosomes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Sheth, Jayesh ; Bhavsar, Riddhi ; Mistri, Mehul ; Pancholi, Dhairya ; Bavdekar, Ashish ; Dalal, Ashwin ; Ranganath, Prajnya ; Girisha, Katta M. ; Shukla, Anju ; Phadke, Shubha ; Puri, Ratna ; Panigrahi, Inusha ; Kaur, Anupriya ; Muranjan, Mamta ; Goyal, Manisha ; Ramadevi, Radha ; Shah, Raju ; Nampoothiri, Sheela ; Danda, Sumita ; Datar, Chaitanya ; Kapoor, Seema ; Bhatwadekar, Seema ; Sheth, Frenny. / Gaucher disease : Single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation 06 Biological Sciences 0601 Biochemistry and Cell Biology. In: BMC Medical Genetics. 2019 ; Vol. 20, No. 1.
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title = "Gaucher disease: Single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation 06 Biological Sciences 0601 Biochemistry and Cell Biology",
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.",
author = "Jayesh Sheth and Riddhi Bhavsar and Mehul Mistri and Dhairya Pancholi and Ashish Bavdekar and Ashwin Dalal and Prajnya Ranganath and Girisha, {Katta M.} and Anju Shukla and Shubha Phadke and Ratna Puri and Inusha Panigrahi and Anupriya Kaur and Mamta Muranjan and Manisha Goyal and Radha Ramadevi and Raju Shah and Sheela Nampoothiri and Sumita Danda and Chaitanya Datar and Seema Kapoor and Seema Bhatwadekar and Frenny Sheth",
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doi = "10.1186/s12881-019-0759-1",
language = "English",
volume = "20",
journal = "BMC Medical Genetics",
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Sheth, J, Bhavsar, R, Mistri, M, Pancholi, D, Bavdekar, A, Dalal, A, Ranganath, P, Girisha, KM, Shukla, A, Phadke, S, Puri, R, Panigrahi, I, Kaur, A, Muranjan, M, Goyal, M, Ramadevi, R, Shah, R, Nampoothiri, S, Danda, S, Datar, C, Kapoor, S, Bhatwadekar, S & Sheth, F 2019, 'Gaucher disease: Single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation 06 Biological Sciences 0601 Biochemistry and Cell Biology', BMC Medical Genetics, vol. 20, no. 1, 31. https://doi.org/10.1186/s12881-019-0759-1

Gaucher disease : Single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation 06 Biological Sciences 0601 Biochemistry and Cell Biology. / Sheth, Jayesh; Bhavsar, Riddhi; Mistri, Mehul; Pancholi, Dhairya; Bavdekar, Ashish; Dalal, Ashwin; Ranganath, Prajnya; Girisha, Katta M.; Shukla, Anju; Phadke, Shubha; Puri, Ratna; Panigrahi, Inusha; Kaur, Anupriya; Muranjan, Mamta; Goyal, Manisha; Ramadevi, Radha; Shah, Raju; Nampoothiri, Sheela; Danda, Sumita; Datar, Chaitanya; Kapoor, Seema; Bhatwadekar, Seema; Sheth, Frenny.

In: BMC Medical Genetics, Vol. 20, No. 1, 31, 14.02.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Gaucher disease

T2 - Single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation 06 Biological Sciences 0601 Biochemistry and Cell Biology

AU - Sheth, Jayesh

AU - Bhavsar, Riddhi

AU - Mistri, Mehul

AU - Pancholi, Dhairya

AU - Bavdekar, Ashish

AU - Dalal, Ashwin

AU - Ranganath, Prajnya

AU - Girisha, Katta M.

AU - Shukla, Anju

AU - Phadke, Shubha

AU - Puri, Ratna

AU - Panigrahi, Inusha

AU - Kaur, Anupriya

AU - Muranjan, Mamta

AU - Goyal, Manisha

AU - Ramadevi, Radha

AU - Shah, Raju

AU - Nampoothiri, Sheela

AU - Danda, Sumita

AU - Datar, Chaitanya

AU - Kapoor, Seema

AU - Bhatwadekar, Seema

AU - Sheth, Frenny

PY - 2019/2/14

Y1 - 2019/2/14

N2 - 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.

AB - 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.

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DO - 10.1186/s12881-019-0759-1

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