Identification of keratan sulfate in liver affected by morquio syndrome

Minami, Ryoji; Abo, Katsuyuki; Kudoh, Tooru; Tsugawa, Satosi; Oyanagi, Kiyomitsu

doi:10.1016/0009-8981(79)90090-1

Cited by 15 publications

(2 citation statements)

References 19 publications

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“…MPS IVA patients experience accumulation of skeletal KS in the liver [41], [42] and some experience hepatomegaly [43]. Our studies revealed significant rhGALNS-A488 delivery in the sinusoidal cells and macrophages of the liver (Kuppfer cells) ( Figure 7A ).…”

Section: Resultsmentioning

confidence: 66%

Enzyme Replacement in a Human Model of Mucopolysaccharidosis IVA In Vitro and Its Biodistribution in the Cartilage of Wild Type Mice

et al. 2010

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Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfatase (GALNS), an enzyme that degrades keratan sulfate (KS). Currently no therapy for MPS IVA is available. We produced recombinant human (rh)GALNS as a potential enzyme replacement therapy for MPS IVA. Chinese hamster ovary cells stably overexpressing GALNS and sulfatase modifying factor-1 were used to produce active (∼2 U/mg) and pure (≥97%) rhGALNS. The recombinant enzyme was phosphorylated and was dose-dependently taken up by mannose-6-phosphate receptor (Kuptake = 2.5 nM), thereby restoring enzyme activity in MPS IVA fibroblasts. In the absence of an animal model with a skeletal phenotype, we established chondrocytes isolated from two MPS IVA patients as a disease model in vitro. MPS IVA chondrocyte GALNS activity was not detectable and the cells exhibited KS storage up to 11-fold higher than unaffected chondrocytes. MPS IVA chondrocytes internalized rhGALNS into lysosomes, resulting in normalization of enzyme activity and decrease in KS storage. rhGALNS treatment also modulated gene expression, increasing expression of chondrogenic genes Collagen II, Collagen X, Aggrecan and Sox9 and decreasing abnormal expression of Collagen I. Intravenous administration of rhGALNS resulted in biodistribution throughout all layers of the heart valve and the entire thickness of the growth plate in wild-type mice. We show that enzyme replacement therapy with recombinant human GALNS results in clearance of keratan sulfate accumulation, and that such treatment ameliorates aberrant gene expression in human chondrocytes in vitro. Penetration of the therapeutic enzyme throughout poorly vascularized, but clinically relevant tissues, including growth plate cartilage and heart valve, as well as macrophages and hepatocytes in wild-type mouse, further supports development of rhGALNS as enzyme replacement therapy for MPS IVA.

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Section: Resultsmentioning

confidence: 66%

Enzyme Replacement in a Human Model of Mucopolysaccharidosis IVA In Vitro and Its Biodistribution in the Cartilage of Wild Type Mice

et al. 2010

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“…Hepatosplenomegaly has also been reported (Holzgreve et al 1981), although it seems to be less common and was not found in all studies in which it was evaluated (Nelson et al 1988). The liver manifestations are likely a direct result of GAG accumulation as keratan sulfate and chondroitin-6-sulfate are known to accumulate in the liver (Minami et al 1979). Interestingly, when analyzed, the keratan sulfate found in the liver of a patient with MPS IVA appeared to be structurally similar to the keratan sulfate found in bone (Minami et al 1983).…”

Section: Clinical Featuresmentioning

confidence: 99%

Clinical overview and treatment options for non‐skeletal manifestations of mucopolysaccharidosis type IVA

Hendriksz

Al-Jawad

Berger

et al. 2012

J of Inher Metab Disea

133

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Mucopolysaccharidosis type IVA (MPS IVA) or Morquio syndrome is a multisystem disorder caused by galactosamine-6-sulfatase deficiency. Skeletal manifestations, including short stature, skeletal dysplasia, cervical instability, and joint destruction, are known to be associated with this condition. Due to the severity of these skeletal manifestations, the non-skeletal manifestations are frequently overlooked despite their significant contribution to disease progression and impact on quality of life. This review provides detailed information regarding the non-skeletal manifestations and suggests long-term assessment guidelines. The visual, auditory, digestive, cardiovascular, and respiratory systems are addressed and overall quality of life as measured by endurance and other functional abilities is discussed. Impairments such as corneal clouding, astigmatism, glaucoma, hearing loss, hernias, hepatomegaly, dental abnormalities, cardiac valve thickening and regurgitation, obstructive sleep apnea, tracheomalacia, restrictive and obstructive respiratory compromise, and muscular weakness are discussed. Increased awareness of these non-skeletal features is needed to improve patient care.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-012-9459-0) contains supplementary material, which is available to authorized users.

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Orthopedic surgery

1983

Arthritis & Rheumatism

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Identification of keratan sulfate in liver affected by morquio syndrome

Cited by 15 publications

References 19 publications

Enzyme Replacement in a Human Model of Mucopolysaccharidosis IVA In Vitro and Its Biodistribution in the Cartilage of Wild Type Mice

Enzyme Replacement in a Human Model of Mucopolysaccharidosis IVA In Vitro and Its Biodistribution in the Cartilage of Wild Type Mice

Clinical overview and treatment options for non‐skeletal manifestations of mucopolysaccharidosis type IVA

Orthopedic surgery

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