Pathology of the first autopsy case diagnosed as mucolipidosis type III α/β suggesting autophagic dysfunction

Kobayashi, Hiroshi; Takahashi‐Fujigasaki, Junko; Fukuda, Takahiro; Sakurai, Ken; Shimada, Yohta; Nomura, Koichi; Ariga, Masamichi; Ohashi, Toya; Eto, Yoshikatsu; Otomo, Takanobu; Sakai, Norio; Ida, Hiroyuki

doi:10.1016/j.ymgme.2010.09.014

Cited by 18 publications

(16 citation statements)

References 19 publications

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“…In the case of ML-II, autophagic and mitochondrial impairment has been reported in skin fibroblasts, mice, and an autopsy case (20,31,32). Autophagic status and mitochondrial structure recovered after enzyme treatment of ML-II cells in our study.…”

Section: Cellular Dysfunction In Ml-iisupporting

confidence: 68%

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: Cellular Dysfunction In Ml-iisupporting

confidence: 68%

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 qualitative degrading and dysfunction of soft connective tissue adversely affects not only periarticular and peri-osseous structures, but also bronchopulmonary elasticity and cardiac valve anatomy and function, ultimately contributing to lethal outcome. 2 Elucidation of the mechanisms by which this mutation leads to partial 'uncoupling' of the severe physical impact and the rather moderate cognitive disability in this specific intermediate ML will expand understanding of pathogenesis of ML beyond inadequately phosphorylated glycoproteins.…”

Section: Discussionmentioning

confidence: 99%

“…1 The postmortem study of patient 3 was recently published as the report of autopsy findings in a patient with ML IIIa/b. 2 Patients 4-8 are siblings. The earlier part of the disorder's course in the older siblings was reported by Kozlowski et al 3 All sibs were included in the recent report by David-Vizcarra et al, 4 who recognized the affected as examples of ML intermediate between ML II and ML IIIab.…”

Section: Methodsmentioning

confidence: 99%

A novel intermediate mucolipidosis II/IIIαβ caused by GNPTAB mutation in the cytosolic N-terminal domain

et al. 2013

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Mucolipidosis (ML) II and ML IIIa/b are allelic autosomal recessive metabolic disorders due to mutations in GNPTAB. The gene encodes the enzyme UDP-GlcNAc-1-phosphotransferase (GNPT), which is critical to proper trafficking of lysosomal acid hydrolases. The ML phenotypic spectrum is dichotomous. Criteria set for defining ML II and ML IIIa/b are inclusive for all but the few patients with phenotypes that span the archetypes. Clinical and biochemical findings of the 'intermediate' ML in eight patients with the c.10A4C missense mutation in GNPTAB are presented to define this intermediate ML and provide a broader insight into ML pathogenesis. Extensive clinical information, including radiographic examinations at various ages, was obtained from a detailed study of all patients. GNPTAB was sequenced in probands and parents. GNPT activity was measured and cathepsin D sorting assays were performed in fibroblasts. Intermediate ML patients who share the c.10A4C/p.K4Q mutation in GNPTAB demonstrate a distinct, consistent phenotype similar to ML II in physical and radiographic features and to ML IIIa/b in psychomotor development and life expectancy. GNPT activity is reduced to 7-12% but the majority of newly synthesized cathepsin D remains intracellular. The GNPTAB c.10A4C/p.K4Q missense allele results in an intermediate ML II/III with distinct clinical and biochemical characteristics. This delineation strengthens the utility of the discontinuous genotypephenotype correlation in ML II and ML IIIa/b and prompts additional studies on the tissue-specific pathogenesis in GNPT-deficient ML.

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“…In contrast, no variations in the levels of BECN1 are observed, suggesting that formation of autophagosomes is not increased in these disorders 22 . Accumulation of LC3-positive structures and ubiquitin aggregates is also reported in neuronal cells of dorsal root ganglions in a MLIII patient 23 . Importantly, inhibition of autophagy restores mitochondrial alterations in MLII and MLIII cells, thus suggesting that increased autophagy might be detrimental for proper mitochondrial function 22 …”

Section: Autophagy In Mucolipidosismentioning

confidence: 99%

Autophagy in lysosomal storage disorders

et al. 2012

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Lysosomes are ubiquitous intracellular organelles that have an acidic internal pH, and play crucial roles in cellular clearance. Numerous functions depend on normal lysosomes, including the turnover of cellular constituents, cholesterol homeostasis, downregulation of surface receptors, inactivation of pathogenic organisms, repair of the plasma membrane and bone remodeling. Lysosomal storage disorders (LSDs) are characterized by progressive accumulation of undigested macromolecules within the cell due to lysosomal dysfunction. As a consequence, many tissues and organ systems are affected, including brain, viscera, bone and cartilage. The progressive nature of phenotype development is one of the hallmarks of LSDs. In recent years biochemical and cell biology studies of LSDs have revealed an ample spectrum of abnormalities in a variety of cellular functions. These include defects in signaling pathways, calcium homeostasis, lipid biosynthesis and degradation and intracellular trafficking. Lysosomes also play a fundamental role in the autophagic pathway by fusing with autophagosomes and digesting their content. Considering the highly integrated function of lysosomes and autophagosomes it was reasonable to expect that lysosomal storage in LSDs would have an impact upon autophagy. The goal of this review is to provide readers with an overview of recent findings that have been obtained through analysis of the autophagic pathway in several types of LSDs, supporting the idea that LSDs could be seen primarily as “autophagy disorders.”

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Pathology of the first autopsy case diagnosed as mucolipidosis type III α/β suggesting autophagic dysfunction

Cited by 18 publications

References 19 publications

Lysosomal Storage Causes Cellular Dysfunction in Mucolipidosis II Skin Fibroblasts

Lysosomal Storage Causes Cellular Dysfunction in Mucolipidosis II Skin Fibroblasts

A novel intermediate mucolipidosis II/IIIαβ caused by GNPTAB mutation in the cytosolic N-terminal domain

Autophagy in lysosomal storage disorders

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