Abstract
Gaucher disease (GD) is the most common glycolipid storage disorder resulting from glucocerebrosidase deficiency due to mutations in the GBA gene. Study was performed in 33 unrelated patients with low β-glucosidase activity in leukocytes and/or fibroblasts. The exons and exon–intron boundaries of the GBA gene were bidirectionally sequenced using an automated sequencer. Mutations were confirmed in parents and were looked up in public databases, and in silico analysis was carried for novel mutations. We identified two novel missense mutations G289A (c.866G>C) and I466S (c.1397T>G) in exons 7 and 10, respectively, in two (6.06%) patients that destabilize the protein structure. L444P (c.1448T>C) was the most common mutation identified in 20/33 (60.60%) non-neuronopathic and 1/33 (3.03%) sub-acute neuronopathic form based on clinical presentation at the time of investigation. Other nine rare mutations were: R463C (c.1504C>T), R395C (c.1300C>T), R359Q (c.1193G>A), G355D (c.1181G>A), V352M (c.1171G>A) and S356F (c.1184C>T) found in each patient (18.18%). Compound heterozygous mutation L444P (c.1448T>C)/R496C (c.1603C>T) in exon 10/11 and L444P (c.1448T>C)/R329C (c.1102C>T) were observed in exon 10/8 in one each patient (6.06%). Two patients (6.06%) from Sri Lanka showed E326K (c.1093G>A) mutation in exon 8. We conclude that L444P is the most common mutant allele with exons 8 and 10 as the hot spot region of GBA gene observed in Indian GD patients.
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Acknowledgements
We are grateful to the patients and their families who kindly agreed to participate in this study. We also thank all clinicians for referring patients to our center. We gratefully acknowledge the financial support by Indian Council of Medical Research grant no. BMS- 54/2010 for enzymes study and Foundation of Research in Genetics and Endocrinology for molecular study.
Author contributions
JS was involved in the designing of the study, standardization of technical procedure, preparation of manuscript and will also act as a guarantor. CA was involved in processing the sample, standardization of molecular techniques and preparation of the manuscript. MAM was involved in processing of sample for enzymes study. PT helped in the standardization of molecular technique by providing positive controls and independently confirmed L444P mutation in four samples. PT and FS have critically evaluated the manuscript. VK helped in protein modeling of novel mutations. AB, MM, UD, SN, SEK were involved in clinical data collection. SG helped in technical support. All the authors read and approved the manuscript.
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Jayesh Sheth is a scientific adviser to the Genzyme Sanofi India. While other authors have no conflict of interest.
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Ankleshwaria, C., Mistri, M., Bavdekar, A. et al. Novel mutations in the glucocerebrosidase gene of Indian patients with Gaucher disease. J Hum Genet 59, 223–228 (2014). https://doi.org/10.1038/jhg.2014.5
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DOI: https://doi.org/10.1038/jhg.2014.5
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