Novel subtype of mucopolysaccharidosis caused by arylsulfatase K (ARSK) deficiency

Abstract

BackgroundMucopolysaccharidoses (MPS) are monogenic metabolic disorders that significantly affect the skeleton. Eleven enzyme defects in the lysosomal degradation of glycosaminoglycans (GAGs) have been assigned to the known MPS subtypes (I–IX). Arylsulfatase K (ARSK) is a recently characterised lysosomal hydrolase involved in GAG degradation that removes the 2-O-sulfate group from 2-sulfoglucuronate. Knockout of Arsk in mice was consistent with mild storage pathology, but no human phenotype has yet been described.MethodsIn this study, we report four affected individuals of two unrelated consanguineous families with homozygous variants c.250C>T, p.(Arg84Cys) and c.560T>A, p.(Leu187Ter) in ARSK, respectively. Functional consequences of the two ARSK variants were assessed by mutation-specific ARSK constructs derived by site-directed mutagenesis, which were ectopically expressed in HT1080 cells. Urinary GAG excretion was analysed by dimethylene blue and electrophoresis, as well as liquid chromatography/mass spectrometry (LC-MS)/MS analysis.ResultsThe phenotypes of the affected individuals include MPS features, such as short stature, coarse facial features and dysostosis multiplex. Reverse phenotyping in two of the four individuals revealed additional cardiac and ophthalmological abnormalities. Mild elevation of dermatan sulfate was detected in the two subjects investigated by LC-MS/MS. Human HT1080 cells expressing the ARSK-Leu187Ter construct exhibited absent protein levels by western blot, and cells with the ARSK-Arg84Cys construct showed markedly reduced enzyme activity in an ARSK-specific enzymatic assay against 2-O-sulfoglucuronate-containing disaccharides as analysed by C18-reversed-phase chromatography followed by MS.ConclusionOur work provides a detailed clinical and molecular characterisation of a novel subtype of mucopolysaccharidosis, which we suggest to designate subtype X.

Mucopolysaccharidoses and the blood–brain barrier

“…The enzyme ARSK, first identified by Wiegmann et al is a lysosomal enzyme that hydrolyzes the sulfate esters moieties found on GAGs [ 15 ]. Due to the novelty of this finding, human patients eluded diagnosis until very recently when Verheyen et al [ 16 ] located four patients from two different families in two different countries. Two variants of the enzyme ARSK deficiency were observed: a c.250C > T, p.(Arg84Cys) mutation seen in two children of a Turkish family, and a c.560T > A, p.(Leu187Ter) mutation in two children of an Indian family.…”

“…While both variants had skeletal abnormalities, including short trunk statures, genu valgum, and coarse facial features, the two variants had some differences. For example, individuals with the c.250C > T mutation had cardiac and mild ocular abnormalities, whereas one of the individuals with a c.560T > A presented with brachydactyly and renal calculi [ 16 ]. More investigation is necessary as the sample size is limited preventing further characterization of symptom presentation in MPS type X patients.…”

Unmet Cardiac Clinical Needs in Adult Mucopolysaccharidoses

“…The MPSs (types I, II, III, IV, VI, VII, and X) are caused by deficiencies of type-specific lysosomal enzymes leading to excessive deposition of glycosaminoglycans (GAGs) in cardiovascular, skeletal and central nervous system tissues that ultimately affects their function (5,6). Severe forms of MPS are often identified in infancy or childhood while attenuated forms may not be found until adolescence or adulthood, if at all.…”

Editorial: Molecular Aspects of Mucopolysaccharidoses

“…Mucopolysaccharidoses (MPS) are a group of 13 diseases (see Table 1 for details) belonging to lysosomal storage disorders (LSD) that occur with cumulative frequencies of all their types of about 1 per 40,000—50,000 live births ( Çelik et al, 2021 ). Out of these 13 types of MPS, 11 are known since many years, while 2 types were discovered recently, MPS X ( Verheyen et al, 2022 ) and MPS-plus-syndrome (MPSPS) ( Vasilev et al, 2020 ). All MPS diseases are caused by mutations in genes coding for enzymes involved in metabolism (usually catabolism) of glycosaminoglycans (GAGs) (formerly called mucopolysaccharides).…”

“… a Summary on mucopolysaccharidoses I-IX was presented by Tomatsu et al (2018) , MPS X has been discovered recently by Verheyen et al (2022) , and MPS-plus-syndrome (MPSPS) was characterized recently by Vasilev et al (2020) (note that an MPS plus-like syndrome has been described in patients with mutations in the VPS16 gene, coding for vacuolar protein sorting protein 16; Yıldız et al, 2021 ). …”