Recurrent and novel GLB1 mutations in India

  • Gene. 2015 Aug 10;567(2):173-81. doi: 10.1016/j.gene.2015.04.078.
Abdul Mueed Bidchol  1 ,  Ashwin Dalal  2 ,  Rakesh Trivedi  3 ,  Anju Shukla  1 ,  Sheela Nampoothiri  4 ,  V H Sankar  5 ,  Sumita Danda  6 ,  Neerja Gupta  7 ,  Madhulika Kabra  7 ,  Shrikiran A Hebbar  8 ,  Ramesh Y Bhat  8 ,  Divya Matta  2 ,  Alka V Ekbote  6 ,  Ratna Dua Puri  9 ,  Shubha R Phadke  10 ,  Kalpana Gowrishankar  11 ,  Shagun Aggarwal  12 ,  Prajnya Ranganath  12 ,  Sheetal Sharda  13 ,  Mahesh Kamate  14 ,  Chaitanya A Datar  15 ,  Kamalakshi Bhat  16 ,  Nutan Kamath  16 ,  Hitesh Shah  17 ,  Shuba Krishna  18 ,  Puthiya Mundyat Gopinath  19 ,  Ishwar C Verma  9 ,  H A Nagarajaram  20 ,  Kapaettu Satyamoorthy  19 ,  Katta Mohan Girisha  21
Affiliations
  • 1. Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.
  • 2. Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
  • 3. Laboratory of Computational Biology & Bioinformatics Facility, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India; Graduate Studies, Manipal University, Manipal, Karnataka, India.
  • 4. Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Center, Kochi, AIMS Ponekkara, Kerala, India.
  • 5. Genetic Clinic, Department of Pediatrics, SAT Hospital, Government Medical College, Thiruvananthapuram, Kerala, India.
  • 6. Department of Clinical Genetics, Christian Medical College and Hospital, Vellore, Tamil Nadu, India.
  • 7. Genetics Unit, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
  • 8. Department of Pediatrics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.
  • 9. Center of Medical Genetics, Sir Ganga Ram Hospital, New Delhi, India.
  • 10. Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
  • 11. Department of Medical Genetics, Childs Trust Medical Research Foundation, Kanchi Kamakoti Childs Trust Hospital, Chennai, Tamil Nadu, India.
  • 12. Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India; Department of Medical Genetics, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India.
  • 13. Post Graduate Institute of Medical Education and Research, Chandigarh, Punjab, India.
  • 14. Pediatric Neurology, KLE University's J N Medical College, Belgaum, Karnataka, India.
  • 15. Rare Genetic Disorder Clinic, Sahyadri Hospital, Pune, Maharashtra, India.
  • 16. Department of Pediatrics, Kasturba Medical College, Mangalore, Manipal University, Karnataka, India.
  • 17. Pediatric Orthopedics Services, Department of Orthopedics, Kasturba Medical College, Manipal, Manipal University, Karnataka, India.
  • 18. Strand Life Sciences Pvt Ltd, Bengaluru, Karnataka, India.
  • 19. Division of Biotechnology, School of Life Sciences, Manipal University, Manipal, Karnataka, India.
  • 20. Laboratory of Computational Biology & Bioinformatics Facility, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
  • 21. Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India. Electronic address: [email protected].
PMID: 25936995 DOI: 10.1016/j.gene.2015.04.078
Abstract

GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in the GLB1 gene, leading to the deficiency of the enzyme β-d-galactosidase. In this study, we report molecular findings in 50 Asian Indian families with GM1 gangliosidosis. We sequenced all the exons and flanking intronic sequences of GLB1 gene. We identified 33 different mutations (20 novel and 13 previously reported). The novel mutations include 12 missense (p.M1?, p.E129Q, p.G134R, p.L236P, p.G262E, p.L297F, p.Y331C, p.G414V, p.K493N, p.L514P, p.P597L, p.T600I), four splicing (c.246-2A>G, c.397-2A>G, c.552+1G>T, c.956-2A>G), three indels (p.R22Qfs*8, p.L24Cfs*47, p.I489Qfs*4) and one nonsense mutation (p.Q452*). Most common mutations identified in this study were c.75+2InsT (14%) and p.L337P (10%). Known mutations accounted for 67% of allele frequency in our cohort of patients, suggesting that these mutations in GLB1 are recurrent across different populations. Twenty three mutations were localized in the TIM barrel domain, β-domain 1 and β-domain 2. In silico sequence and structure analysis of GLB1 reveal that all the novel mutations affect the function and structure of the protein. We hereby report on the largest series of patients with GM1 gangliosidosis and the first from India.

Keywords
GLB1 gene; GM1 gangliosidosis; India; Mutation.