Sudha Srinivasan

Ph.D,Indian Institute of Science, Bengaluru

Post-Doctoral Fellowship, Duke University Medical Centre, Durham, USA
Post-Doctoral Fellowship, University of Illinois, USA.

My lab studies two specific groups of monogenic disorders of carbohydrate metabolism: mucopolysaccharidoses (MPS) and maturity onset diabetes of the young (MODY). Soon, we will also take up studies on certain genetic aspects of diabetic retinopathy.

MPS is a group of recessive disorders characterised by mutations in any of the genes that when mutated result in deficient activity of an enzyme that catalyses a critical step in the intra-lysosomal degradation of glycosaminoglycans (GAGs). The defect leads to excessive intra-lysosomal accumulation of GAGs, resulting in disease. Eleven genes are known, any of which when mutated results in an MPS disorder. MPS II is X-linked, the rest are autosomal recessive. Enzyme replacement therapy is available for a few MPS types.

Our study is aimed at identification of mutations that lead to MPS in Indian patients and to understand, using computational tools, how the mutations lead to disease. We do this work in collaboration with many physicians, notably Dr.Sujatha M Jagadeesh (Chennai) and Dr. Sheela Nampoothiri (Kochi). The computational studies are performed in collaboration with Dr. S Thiyagarajan, Institute of Bioinformatics and Applied Biotechnology (IBAB), Bengaluru.

Our study of MPS disorders has yielded new knowledge on mutations underlying various types of MPS. An example of mutations we have found in MPS VI patients is shown in the figure. In the various MPS types we have studied, we have identified some common mutations, novel mutations, and mutations found so far only in India.We have also found not able regional differences in occurrence of mutations in one particular type of MPS, MPS IVA.

The earlier part of the study was funded by individual research grants from Government of India's Department of Biotechnology (DBT) and Department of Science and Technology (DST).Currently, the study is being funded by CHG and a core grant to CHG from Indian Council of Medical Research (ICMR).The term MODY refers to specific types of diabetes mellitus (MODY 1, MODY 2, and so on) distinct from the more common types, namely type 1 and type 2 diabetes. The MODY disorders are inheritedin an autosomal dominant manner. Age of onset is generally less than that in type 2 diabetes. Thus,even though MODY is rare, its burden is high.Currently, many MODY patients are misdiagnosed as having other types of diabetes. Diagnosing MODY is important because, in certain types of MODY, treatment is guided by the type of MODY.

We have just initiated studies on determining the prevalence of MODY among diabetic patients presenting themselves in a tertiary care hospital in Bengaluru.

We will use a combination of approaches to accomplish this- clinical, biochemical and genetic. The study is being conducted in collaboration with Dr. R Anil Kumar and other physicians in Karnataka Institute of Endocrinology and Research, Bengaluru, with funding from Rajiv Gandhi University of Health Sciences (RGUHS), Bengaluru.As MODY is little-studied, our research in this area would enable us to make valuable contributions to our knowledge of these rare forms of diabetes.

Mutations found in this study of MPS VI patients

Selected publications:

1.The promise of discovering population-specific disease-associated genes in South Asia. Nature Genetics, 49: 1403-1407 (2017). Nakatsuka N, Moorjani P, Rai N, Sarkar B, Tandon A, Patterson N, Bhavani GS, Girisha KM, Mustak MS, Srinivasan S, Kaushik A, Vahab SA, Jagadeesh SM, Satyamoorthy K, Singh L, Reich D, Thangaraj K

2.ENG, ACVRL1, SMAD4, and hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome). In 'Epstein's Inborn Errors of Development: the Molecular Basis of Clinical Disorders of Morphogenesis', 3rd edition. Eds. RP Erickson and AJ Wynshaw-Boris. Oxford University Press (2016). Srinivasan S, Berg JN, Marchuk DA .

3.Mutations in ARSB in MPS VI patients in India.Molecular Genetics and Metabolism Reports, 4: 53-61 (2015). Mathew J, Jagadeesh SM, Bhat M, Udhaya Kumar S, Thiyagarajan S, Srinivasan S.

4.Deficits in reproduction and progonadotrophin- releasing hormone processing in male Cpefat mice.Endocrinology,145: 2023-2034 (2004). Srinivasan S, Bunch DO, Feng Y, Rodriguiz RM, Li M, Ravenell RL, Luo GX, Arimura A, Fricker LD, Eddy EM,Wetsel WC.