Mutational analysis of ARSB gene in mucopolysaccharidosis type VI: identification of three novel mutations in Iranian patients

Document Type: Original Article

Authors

1 Department of Human Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Islamic Republic of Iran

2 Division of Endocrinology and Metabolism, Department of Pediatrics, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Islamic Republic of Iran

Abstract

Objective(s): Mucopolysaccharidosis VI (MPS VI) or Maroteaux-Lamy syndrome is a rare metabolic disorder, resulting from the deficient activity of the lysosomal enzyme arylsulfatase B (ARSB).  The enzymatic defect of ARSB leads to progressive lysosomal storage disorder and accumulation of glycosaminoglycan (GAG) dermatan sulfate (DS), which causes harmful effects on various organs and tissues and short stature. To date, more than 160 different mutations have been reported in the ARSB gene.
Materials and Methods: Here, we analyzed 4 Iranian and 2 Afghan patients, with dysmorphism indicating MPS VI from North-east Iran. To validate the patients’ type of MPS VI, urine mucopolysaccharide and leukocyte ARSB activity were determined. Meanwhile, genomic DNA was amplified for all 8 exons and flanking intron sequences of the ARSB gene to analyze the spectrum of mutations responsible for the disorder in all patients.
Results: Abnormal excretion of DS and low leukocyte ARSB activity were observed in the urine samples of all 6 studied patients. In direct DNA sequencing, we detected four different homozygous mutations in different exons, three of which seem not to have been reported previously: p.H178N, p.H242R, and p.*534W. All three novel substitutions were found in patients with Iranian breed. We further detected the IVS5+2T>C mutation in Afghan siblings and four different homozygous polymorphisms, which have all been observed in other populations.  
Conclusion: results indicated that missense mutations were the most common mutations in the ARSB gene, most of them being distributed throughout the ARSB gene and restricted to individual families, reflecting consanguineous marriages.

Keywords

Main Subjects


1. Krenzlin H, Tan TC, Lampe C, Lampe C, Knuf M, Horn P,                    et al. Standalone cranio-cervical decompression is feasible in children with mucopolysaccharidosis type I, IVA and VI.  Spine J 2018; 18: 30135-30139.
2. Maroteaux P, Leveque B, Marie J, Lamy M. [A new dysostosis with urinary elimination of chondroitin sulfate b. Presse Med 1963; 71:1849-1852.
3. de Almeida-Barros RQ, de Medeiros PFV, de Almeida Azevedo MQ, de Oliveira Lira Ortega A, Yamamoto ATA, Dornelas SKL, et al. Evaluation of oral manifestations of patients with mucopolysaccharidosis IV and VI: clinical and imaging study. Clin Oral Investig 2018; 22:201-208.
4.    Zanetti A, Onenli-Mungan N, Elcioglu N, Ozbek MN, Kor D, Lenzini E, et al. Molecular analysis of Turkish maroteaux-lamy patients and identification of one novel mutation in the arylsulfatase B (ARSB) gene. JIMD Rep 2014; 14:1-9.
5.    Melbouci M, Mason RW, Suzuki Y, Fukao T, Orii T, Tomatsu S. Growth impairment in mucopolysaccharidoses. Mol Genet Metab 2018.
6.    Lin WD, Lin SP, Wang CH, Hwu WL, Chuang CK, Lin SJ, et al. Genetic analysis of mucopolysaccharidosis type VI in Taiwanese patients. Clin Chim Acta 2008; 394:89-93.
7.    Saito S, Ohno K, Sugawara K, Sakuraba H. Structural and clinical implications of amino acid substitutions in N-acetylgalactosamine-4-sulfatase: insight into mucopolysaccharidosis type VI. Mol Genet Metab 2008; 93:419-425.
8.    Brooks DA, McCourt PA, Gibson GJ, Ashton LJ, Shutter M, Hopwood JJ. Analysis of N-acetylgalactosamine-4-sulfatase protein and kinetics in mucopolysaccharidosis type VI patients. Am J Hum Genet 1991; 48:710-719.
9.    Yassaee VR, Hashemi-Gorji F, Miryounesi M, Rezayi A, Ravesh Z, Yassaee F, et al. Clinical, biochemical and molecular features of Iranian families with mucopolysaccharidosis: A case series. Clin Chim Acta 2017; 474:88-95.
10.    Turbeville S, Nicely H, Rizzo JD, Pedersen TL, Orchard PJ, Horwitz ME, et al. Clinical outcomes following hematopoietic stem cell transplantation for the treatment of mucopolysaccharidosis VI. Mol Genet Metab 2011; 102:111-115.
11.    Valayannopoulos V, Nicely H, Harmatz P, Turbeville S. Mucopolysaccharidosis VI. Orphanet J Rare Dis 2010; 5:5.
12.    Uttarilli A, Ranganath P, Jain SJ, Prasad CK, Sinha A, Verma IC, et al. Novel mutations of the arylsulphatase B (ARSB) gene in Indian patients with mucopolysaccharidosis type VI. Indian J Med Res 2015; 142:414-425.
13.    Auclair D, Hopwood JJ, Brooks DA, Lemontt JF, Crawley AC. Replacement therapy in mucopolysaccharidosis type VI: advantages of early onset of therapy. Mol Genet Metab 2003; 78:163-174.
14.    Karageorgos L, Brooks DA, Pollard A, Melville EL, Hein LK, Clements PR, et al. Mutational analysis of 105 mucopolysaccharidosis type VI patients. Hum Mutat 2007; 28:897-903.
15.    Litjens T, Baker EG, Beckmann KR, Morris CP, Hopwood JJ, Callen DF. Chromosomal localization of ARSB, the gene for human N-acetylgalactosamine-4-sulphatase. Hum Genet. 1989; 82:67-68.
16.    Litjens T, Hopwood JJ. Mucopolysaccharidosis type VI: Structural and clinical implications of mutations in N-acetylgalactosamine-4-sulfatase. Hum Mutat 2001;18:282-295.
17.    Lin WD, Ke YY, Chou IC, Wang CH, Tsai FJ. Deletion of exon 4 in the N-acetylgalactosamine-4-sulfatase gene in a Taiwanese patient with mucopolysaccharidosis type VI. Tohoku J Exp Med 2015; 235:267-273.
18.    Mathew J, Jagadeesh SM, Bhat M, Udhaya Kumar S, Thiyagarajan S, Srinivasan S. Mutations in ARSB in MPS VI patients in India. Mol Genet Metab Rep 2015; 4:53-61.
19.    Garrido E, Chabas A, Coll MJ, Blanco M, Dominguez C, Grinberg D, et al. Identification of the molecular defects in Spanish and Argentinian mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) patients, including 9 novel mutations. Mol Genet Metab 2007; 92:122-130.
20.     Brands MM, Hoogeveen-Westerveld M, Kroos MA, Nobel W, Ruijter GJ, Ozkan L, et al. Mucopolysaccharidosis type VI phenotypes-genotypes and antibody response to galsulfase. Orphanet J Rare Dis. 2013;8:51.
21.    The Human Gene Mutation Database 2018. Available from: http://www.hgmd.cf.ac.uk/ac/gene.php?gene=ARSB.
22.    Petry MF, Nonemacher K, Sebben JC, Schwartz IV, Azevedo AC, Burin MG, et al. Mucopolysaccharidosis type VI: Identification of novel mutations on the arylsulphatase B gene in South American patients. J Inherit Metab Dis 2005; 28:1027-1034.
23.    Arlt G, Brooks DA, Isbrandt D, Hopwood JJ, Bielicki J, Bradford TM, et al. Juvenile form of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). A C-terminal extension causes instability but increases catalytic efficiency of arylsulfatase B. J Biol Chem 1994; 269:9638-9643.
24.    Hamby SE, Thomas NS, Cooper DN, Chuzhanova N. A meta-analysis of single base-pair substitutions in translational termination codons (‘nonstop’ mutations) that cause human inherited disease. Hum Genomics 2011;5:241-264.
25.    Bond CS, Clements PR, Ashby SJ, Collyer CA, Harrop SJ, Hopwood JJ, et al. Structure of a human lysosomal sulfatase. Structure 1997;5:277-289.
26.    Karageorgos L, Brooks DA, Harmatz P, Ketteridge D, Pollard A, Melville EL, et al. Mutational analysis of mucopolysaccharidosis type VI patients undergoing a phase II trial of enzyme replacement therapy. Mol Genet Metab 2008;90:164-170.