Novel mutations of the arylsulphatase B (ARSB) gene in Indian patients with mucopolysaccharidosis type VI
Anusha Uttarilli1, Prajnya Ranganath2, S Jamal Md Nurul Jain3, C Krishna Prasad3, Anupam Sinha4, Ishwar C Verma5, Shubha R Phadke6, Ratna D Puri5, Sumita Danda7, Mamta N Muranjan8, Ganesh Jevalikar9, HA Nagarajaram4, Ashwin B Dalal3
1 Diagnostics Division, Centre for DNA Fingerprinting & Diagnostics, Hyderabad; Graduate Studies, Manipal University, Manipal, India
2 Diagnostics Division, Centre for DNA Fingerprinting & Diagnostics, Hyderabad; Department of Medical Genetics, Nizam's Institute of Medical Sciences, Hyderabad, India
3 Diagnostics Division, Centre for DNA Fingerprinting & Diagnostics, Hyderabad, India
4 Laboratory of Computational Biology, Centre for DNA Fingerprinting & Diagnostics, Hyderabad, India
5 Center of Medical Genetics, Sir Ganga Ram Hospital, New Delhi, India
6 Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
7 Department of Clinical Genetics, Christian Medical College & Hospital, Vellore, India
8 Department of Pediatrics, Seth G.S. Medical College & KEM Hospital, Mumbai, India
9 Division of Endocrinology & Diabetes, Medanta, Gurgaon, India
Ashwin B Dalal
Diagnostics Division, Centre for DNA Fingerprinting & Diagnostics, 4-1-714, Tuljaguda Complex, Mozamzahi Road, Nampally, Hyderabad 500 001, Telangana
Source of Support: None, Conflict of Interest: None
Background & objectives: Mucopolysaccharidosis type VI (MPS VI) is a rare, autosomal recessive lysosomal storage disorder caused by deficient enzymatic activity of N-acetyl galactosamine-4-sulphatase resulting from mutations in the arylsulphatase B (ARSB) gene. The ARSB gene is located on chromosome 5q11-q13 and is composed of eight exons. More than hundred ARSB mutations have been reported so far, but the mutation spectrum of MPS VI in India is still unknown. Hence, the aim of the present study was to identify the mutational spectrum in patients with MPS VI in India and to study the genotype-phenotype association and functional outcomes of these mutations.
Methods: Molecular characterization of the ARSB gene by Sanger sequencing was done for 15 patients (aged 15 months to 11 yr) who were enzymatically confirmed to have MPS VI. Age of onset, clinical progression and enzyme activity levels in each patient were studied to look for genotype-phenotype association. Haplotype analysis performed for unrelated patients with the recurring mutation W450C, was suggestive of a founder effect. Sequence and structural analyses of the ARSB protein using standard software were carried out to determine the impact of detected mutations on the function of the ARSB protein.
Results: A total of 12 mutations were identified, of which nine were novel mutations namely, p.D53N, p.L98R, p.Y103SfsX9, p.W353X, p.H393R, p.F166fsX18, p.I220fsX5, p.W450L, and p.W450C, and three were known mutations (p.D54N, p.A237D and p.S320R). The nine novel sequence variants were confirmed not to be polymorphic variants by performing sequencing in 50 unaffected individuals from the same ethnic population.
Interpretation & conclusions: Nine novel mutations were identified in MPS VI cases from India in the present study. The study also provides some insights into the genotype-phenotype association in MPS VI.