Mucolipidosis (ML) (OMIM 607840 & 607838) is a rare autosomal recessive inherited disorder that occurs due to the deficiency of golgi enzyme uridine diphosphate (UDP)– N-acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) responsible for tagging mannose-6-phosphate for proper trafficking of lysosomal enzymes to lysosomes. Variants in GlcNAc-phosphotransferase (GNPTAB (α, β subunits) and GNPTG (γ subunits) are known to result in impaired targeting of lysosomal enzymes leading to Mucolipidosis (ML) Type II or Type III. We analyzed 69 Indian families of MLII/III for clinical features and molecular spectrum and performed in silico analysis for novel variants. We identified 38 pathogenic variants in GNPTAB and 5 pathogenic variants in GNPTG genes including missense, frame shift, deletion, duplication and splice site variations. A total of 26 novel variants were identified in GNPTAB and 4 in GNPTG gene. In silico studies using mutation prediction software like SIFT, Polyphen2 and protein structure analysis further confirmed the pathogenic nature of the novel sequence variants detected in our study. Except for a common variant c.3503_3504delTC in early onset MLII, we could not establish any other significant genotype and phenotype correlation. This is one of the largest studies reported till date on Mucolipidosis II/III in order to identify mutation spectrum and any recurrent mutations specific to the Indian ethnic population. The mutational spectrum information in Indian patients will be useful in better genetic counselling, carrier detection and prenatal diagnosis for patients with ML II/III.
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The authors are thankful to the patients and their families who volunteered in the study, for their kind cooperation and for allowing us to use their medical and clinical information for the benefit of others. The authors are glad to acknowledge the support provided by the research institution Centre for DNA Fingerprinting and Diagnostics, Hyderabad. This research project was supported by a research grant from the Indian Council of Medical Research (ICMR)-Department of Health Research, Government of India (GIA/31(Vii)/2014-DHR). Ms. Divya Pasumarthi is the recipient of Senior Research Fellowship (F.NO.45/25/2018-HUM/BMS) from the Indian Council of Medical Research (ICMR). We are grateful to the coordinators and all the members of Task force on Lysosomal storage Disorders of the Indian Council of Medical Research (ICMR)-Department of Health Research, Government of India: Dr. Roli Mathur and Dr. Babbanjee.
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Pasumarthi, D., Gupta, N., Sheth, J. et al. Identification and characterization of 30 novel pathogenic variations in 69 unrelated Indian patients with Mucolipidosis Type II and Type III. J Hum Genet 65, 971–984 (2020). https://doi.org/10.1038/s10038-020-0797-8
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