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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 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 ?-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 ?-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.

SUBMITTER: Sheth J

PROVIDER: S-EPMC6376752 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation.

Sheth Jayesh J Bhavsar Riddhi R Mistri Mehul M Pancholi Dhairya D Bavdekar Ashish A Dalal Ashwin A Ranganath Prajnya P Girisha Katta M KM Shukla Anju A Phadke Shubha S Puri Ratna R Panigrahi Inusha I Kaur Anupriya A Muranjan Mamta M Goyal Manisha M Ramadevi Radha R Shah Raju R Nampoothiri Sheela S Danda Sumita S Datar Chaitanya C Kapoor Seema S Bhatwadekar Seema S Sheth Frenny F

BMC medical genetics 20190214 1

<h4>Background</h4>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 hundr ...[more]

PMID: 30764785

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Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation.

Publications

Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation.

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