Functional characterization of arylsulfatase B mutations in Indian patients with Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI).
MPS VI is an autosomal recessive disorder which occurs due to the deficiency of N-acetyl galactosamine-4-sulfatase (Arylsulfatase B - ARSB) involved in catabolism of dermatan sulfate resulting from disease-causing variations in the ARSB gene. Human Gene Mutation Database (HGMD) search revealed 200 different mutations in ARSB worldwide. In the present study we carried out molecular and functional analyses to characterize the mutations reported by us in Indian population. Mutation analysis of 19 MPS VI patients revealed presence of a total of 15 different mutations of which twelve were novel [p.Asp53Asn (c.157G>A; p.D53N), p.Leu98Arg (c.293T>G; p.L98R), p.Tyr103Serfs*9 (c.306_312delCTACCAG+146del; p.Y103Sfs*9), p.Phe166Leufs*18 (c.496delT; p.F166Lfs*18), p.Ile220Serfs*5 (c.659_660delTA; p.I220Sfs*5), p.Ile350Phe (c.1048A>T; p.I350F), p.Trp353* (c.1059G>A; p.W353*), p.His393Arg (c.1178A>G; p.H393R), p.Ser403Tyrfs* (c.1208delC; p.S403Yfs*), p.Pro445Leu (c.1334C>T; p.P445L), p.Trp450Leu (c.1349G>T; p.W450L) and p.Trp450Cys (c.1350G>C; p.W450C)] and three were known mutations [p.Asp54Asn (c.160G>A; p.D54N), p.Ala237Asp (c.710C>A; p.A237D) and p.Ser320Arg (c.960C>G; p.S320R)]. Functional characterization using site-directed mutagenesis followed by cell transfection assays, immunoblot, reverse transcriptase PCR and immunofluorescence studies for the putative pathogenic variants detected in our MPS VI patient cohort helped us to confirm the pathogenic potential of the variants in ARSB.
Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India; Graduate Studies, Manipal University, Manipal, Karnataka, India.
Anusha
A
Uttarilli
Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
Divya
D
Pasumarthi
Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India; Department of Medical Genetics, Nizam's institute of Medical Sciences, Hyderabad, Telangana, India.
Prajnya
P
Ranganath
Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India. Electronic address: ashwindalal@gmail.com.
Ashwin B
AB
Dalal
D000293:Adolescent; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007194:India; D007223:Infant; D008297:Male; D009087:Mucopolysaccharidosis VI / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D050505:Mutant Proteins; D011994:Recombinant Proteins; D020051:N-Acetylgalactosamine-4-Sulfatase; C581941:ARSB protein, human
Functional characterization; Genotype-phenotype correlation; Molecular analysis; Mucopolysaccharidoses type VI; Novel mutation; Pathogenic variant