Deletion of Exon 4 in the N-Acetylgalactosamine-4-Sulfatase Gene in a Taiwanese Patient with Mucopolysaccharidosis Type VI

Abstract

Mucopolysaccharidosis type VI (MPS VI) is a rare autosomal recessive disorder caused by a deficiency of N-acetylgalactosamine-4-sulfatase (ARSB), one of the enzymes required for the degradation of dermatan sulfate (DS). Accumulation of DS in connective tissue causes growth failure, resulting in short stature. Here, we observed a 5-year-old girl who was the only one affected member of her family and who presented with an exaggerated, convex curvature of the back at the age of one year. Abnormal excretion of DS in the urine and extremely low leukocyte ARSB activity were noted. The patient was suspected to have MPS VI. Direct DNA sequencing indicated that there was no mutation in the coding region of ARSB. However, RT-PCR analysis of RNA prepared from blood samples indicated the deletion of the entire exon 4. Further analysis of the genomic DNA by quantitative PCR confirmed a homozygous deletion of exon 4, an unusual intragenic deletion in ARSB. The deletion led to a truncated protein that lacks most of the catalytic domain. The patient received recombinant human ARSB as enzyme replacement therapy (ERT) at an early stage (2 years), and responded positively in terms of skeletal development and other developmental milestones. The early identification of type VI MPS patients and subsequent treatment with ERT may be beneficial for the clinical outcome of MPS VI patients. In addition, detailed gene analysis may enhance the ability to provide genetic counseling to families of patients affected by MPS VI.

Epidemiology of Mucopolysaccharidoses Update

“…c.1072G/A (p.V358M) and c.1191A/G (p.P397P) polymorphisms were detected earlier in MPS VI patients in Taiwan. Although the prevalence of MPS VI is lower (three patients diagnosed with MPS VI in 11 years; one in 875,000 newborns), the variety of mutations is much greater in Taiwan [ 126 , 127 , 128 , 129 ]. Research conducted in Brazil indicated that the p.H178L missense mutation had a founder effect on Brazilian MPS VI patients.…”

Detection of Structural Variants by NGS: Revealing Missing Alleles in Lysosomal Storage Diseases

“…CNVs in MPS-related genes have been characterized and encompass: (i) deletion of exon 14-3′UTR, and duplication of exon 2-intron 12 in IDUA in patients affected by MPS I [ 42 , 43 ]; (ii) deletion of SGSH exons 1–5 in MPS IIIA patients [ 44 ]; (iii) Alu -mediated deletion of NAGLU exons 3–4 in patients with MPS IIIB/Sanfilippo type B syndrome [ 45 , 46 ]; (iv) heterozygous deletion of exon 15 [ 47 ] and homozygous deletion of exons 9–10 in HGSNAT in MPS IIIC or Sanfilippo type C patients [ 43 ]; (v) deletions of GNS exon 1, 2–3, 6–7, 9–14 in patients affected by MPS IIID/Sanfilippo disease type D [ 48 , 49 ]; (vi) deletion of multiple contiguous exons including 1–3, 2–4, 2–5, 3–14, 5–8, 9–14, 10–14, 11–12, and single exon 5 and 13 of GALNS in patients with MPS IVA/Morquio A [ 43 , 50 , 51 , 52 , 53 ]; (vii) ARSB deletion of exons 2–3, exon 4 and exon 5 MPS VI patients [ 54 , 55 , 56 ].…”

Mucopolysaccharidosis type VI (MPS VI) and molecular analysis: Review and classification of published variants in theARSBgene

“…A deletion of exon 4 [c.(690+1_691‐1)_(898+1_899‐1)del; breakpoints unknown] in its entirety was reported in homozygosity in one female Taiwanese individual. This deletion is expected to result in frameshift, premature truncation, and loss of significant portions of the catalytic domain (Lin, Ke, Chou, Wang, & Tsai, ). Finally, a genomic deletion of exon 5 [c.(898+1_899‐1)_(1142+1_1143‐1)del] was reported eight times, once in homozygosity in a male Italian individual, who displayed a classical, severe MPS VI phenotype (Ferla et al., ).…”