Mucolipidosis II and III alpha/beta: mutation analysis of 40 Japanese patients showed genotype–phenotype correlation

Otomo, Takanobu; Muramatsu, Takaki; Yorifuji, Tohru; Okuyama, Torayuki; Nakabayashi, Hiroki; Fukao, Toshiyuki; Ohura, Toshihiro; Yoshino, Makoto; Tanaka, Akemi; Okamoto, Nobuhiko; Inui, Koji; Ozono, Keiichi; Sakai, Norio

doi:10.1038/jhg.2009.3

Cited by 60 publications

(48 citation statements)

References 16 publications

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“…We also purchased two normal skin fibroblast cell lines (HDFn from Invitrogen and NHDF from Lonza). The ML-II patients had typical ML-II phenotype and were diagnosed both enzymatically and genetically (14). Mutations in GNPTAB gene were c.3565CϾT(p.R1189X)/ c.3565CϾT(p.R1189X), c.310CϾT(p.Q104X)/c.3428_3429 insA(p.N1143fs), and c.310CϾT(p.Q104X)/c.2544delA(p.K848fs) in respective ML-II patients.…”

Section: Methodsmentioning

confidence: 99%

Lysosomal Storage Causes Cellular Dysfunction in Mucolipidosis II Skin Fibroblasts

Otomo

Higaki

Nanba

et al. 2011

Journal of Biological Chemistry

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Mucolipidosis II (ML-II) is a fatal inherited metabolic disease caused by deficiency of GlcNAc-phosphotransferase, which plays a role in generating the mannose 6-phosphate recognition marker on lysosomal enzymes. In ML-II, many lysosomal acid hydrolases are mistargeted out of cells, and lysosomes become filled with undigested substrates, which explains inclusion cell disease as an alternative name for this disease. In this study, we revealed various cellular phenotypes in ML-II skin fibroblasts. We quantitated phospholipid and cholesterol within cells and showed ϳ2-fold accumulation in ML-II as compared with normal cells. Lysosomal pH of ML-II cells was higher than that of normal cells (5.29 ؎ 0.08 versus 4.79 ؎ 0.10, p < 0.001). The proliferated lysosomes in ML-II cells were accumulated ϳ3-fold in amount as compared with normal cells. Intracellular logistics including endocytosis and mannose 6-phosphate receptor recycling were impaired in ML-II cells. To confirm whether these ML-II cellular phenotypes derive from deficient lysosomal acid hydrolases within lysosomes, we performed supplementation of lysosomal enzymes using a partially purified total enzyme mixture, which was derived from the conditioned culture medium of normal skin fibroblasts after NH 4 Cl treatment. This supplementation corrected all of the previously described ML-II phenotypes. In addition, the autophagic and mitochondrial impairment that we have previously reported improved, and inclusion bodies disappeared on electron micrography following total lysosomal enzyme supplementation. Our results indicate that various cellular phenotypes in ML-II are caused by the deficiency of many lysosomal enzymes and massive accumulation of undigested substrates.

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Section: Methodsmentioning

confidence: 99%

Lysosomal Storage Causes Cellular Dysfunction in Mucolipidosis II Skin Fibroblasts

Otomo

Higaki

Nanba

et al. 2011

Journal of Biological Chemistry

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“…The exercise-induced increase in plasma free fatty acid and glycerol was decreased due to ATGL deletion, indicating impairment in exercise-induced lipolysis in these mice. ATGL ( 269 ), mucolipidosis ( 270 ), mucopolysaccharidosis, and neuronal ceroid lipofuscinosis. Cardiomyopathy of the three functional types include congestive, as in Fabry disease; hypertrophic, as in glycogen storage disease, type II; and restrictive, as in Gaucher disease ( 271 ).…”

Section: Neutral Lipid Storage Disordersmentioning

confidence: 99%

Delineating the role of alterations in lipid metabolism to the pathogenesis of inherited skeletal and cardiac muscle disorders

Saini-Chohan

Mitchell

Vaz

et al. 2012

Journal of Lipid Research

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“…Mutations in the GNPTAB gene, which encodes the α/β-subunits, are known to be responsible for MLII and MLIIIA [Tiede et al, 2005a and2005b;Kudo et al, 2005;Steet et al, 2005;Paik et al, 2005;Bargal et al, 2006;Tiede et al, 2006;Lam et al, 2007;Otomo et al, 2009]. Mutations in the γ-subunit, encoded by the GNPTG gene (MIM# 607838; chromosome 16p13.3), have been reported to be associated with MLIIIC [Raas-Rothschild et al, 2000Tiede et al, 2004].…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of 22 novel UDP-N-acetylglucosamine-1-phosphate transferase α- and β-subunit (GNPTAB) gene mutations causing mucolipidosis types IIα/β and IIIα/β in 46 patients

et al. 2009

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Mucolipidosis II and III alpha/beta: mutation analysis of 40 Japanese patients showed genotype–phenotype correlation

Cited by 60 publications

References 16 publications

Lysosomal Storage Causes Cellular Dysfunction in Mucolipidosis II Skin Fibroblasts

Lysosomal Storage Causes Cellular Dysfunction in Mucolipidosis II Skin Fibroblasts

Delineating the role of alterations in lipid metabolism to the pathogenesis of inherited skeletal and cardiac muscle disorders

Molecular characterization of 22 novel UDP-N-acetylglucosamine-1-phosphate transferase α- and β-subunit (GNPTAB) gene mutations causing mucolipidosis types IIα/β and IIIα/β in 46 patients

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