Substrate compositional variation with tissue/region and Gba1 mutations in mouse models--implications for Gaucher disease
Ying Sun, Wujuan Zhang, You-Hai Xu, Brian Quinn, Nupur Dasgupta, Benjamin Liou, Kenneth D R Setchell, Gregory A Grabowski, Ying Sun, Wujuan Zhang, You-Hai Xu, Brian Quinn, Nupur Dasgupta, Benjamin Liou, Kenneth D R Setchell, Gregory A Grabowski
Abstract
Gaucher disease results from GBA1 mutations that lead to defective acid β-glucosidase (GCase) mediated cleavage of glucosylceramide (GC) and glucosylsphingosine as well as heterogeneous manifestations in the viscera and CNS. The mutation, tissue, and age-dependent accumulations of different GC species were characterized in mice with Gba1 missense mutations alone or in combination with isolated saposin C deficiency (C*). Gba1 heteroallelism for D409V and null alleles (9V/null) led to GC excesses primarily in the visceral tissues with preferential accumulations of lung GC24∶0, but not in liver, spleen, or brain. Age-dependent increases of different GC species were observed. The combined saposin C deficiency (C*) with V394L homozygosity (4L;C*) showed major GC18:0 degradation defects in the brain, whereas the analogous mice with D409H homozygosity and C* (9H;C*) led to all GC species accumulating in visceral tissues. Glucosylsphingosine was poorly degraded in brain by V394L and D409H GCases and in visceral tissues by D409V GCase. The neonatal lethal N370S/N370S genotype had insignificant substrate accumulations in any tissue. These results demonstrate age, organ, and mutation-specific quantitative differences in GC species and glucosylsphingosine accumulations that can have influence in the tissue/regional expression of Gaucher disease phenotypes.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
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References
- Grabowski GA, Petsko GA, Kolodny EH (2010) Gaucher disease. In: Valle D, Beaudet A, Vogelstein B, Kinzler KW, Antonarakis SE et al..., editors. The Online Metabolic and Molecular Bases of Inherited Diseases. New York: The McGraw-Hill Companies, Inc.
- Hruska KS, LaMarca ME, Scott CR, Sidransky E (2008) Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat 29: 567–583.
- Grabowski GA, Kolodny EH, Weinreb NJ, Rosenbloom BE, Prakash-Cheng A, et al... (2006) Gaucher disease: Phenotypic and genetic variation. Chapter 146.1. In: Scriver CR, Sly WS, Beaudet A, Valle D, Childs B, editors. The Metabolic and Molecular Bases of Inherited Diseases. New York: McGraw-Hill.
- Liou B, Kazimierczuk A, Zhang M, Scott CR, Hegde RS, et al. (2006) Analyses of variant acid beta-glucosidases: effects of Gaucher disease mutations. J Biol Chem 281: 4242–4253.
- Theophilus B, Latham T, Grabowski GA, Smith FI (1989) Gaucher disease: molecular heterogeneity and phenotype-genotype correlations. Am J Hum Genet 45: 212–225.
- Elstein D, Scott CR, Zeigler M, Abrahamov A, Zimran A (2005) Phenotypic heterogeneity in patients with Gaucher disease and the N370S/V394L genotype. Genet Test 9: 26–29.
- Kuske TT, Rosenberg A (1972) Quantity and fatty acyl composition of the glycosphingolipids of Gaucher spleen. J Lab Clin Med 80: 523–529.
- Marinetti GV, Ford T, Stotz E (1960) The structure of cerebrosides in Gaucher’s disease. J Lipid Res 1: 203–207.
- Conradi NG, Sourander P, Nilsson O, Svennerholm L, Erikson A (1984) Neuropathology of the Norrbottnian type of Gaucher disease. Morphological and biochemical studies. Acta Neuropathol 65: 99–109.
- Nilsson O, Svennerholm L (1982) Accumulation of glucosylceramide and glucosylsphingosine (psychosine) in cerebrum and cerebellum in infantile and juvenile Gaucher disease. J Neurochem 39: 709–718.
- Suomi WD, Agranoff BW (1965) Lipids of the Spleen in Gaucher’s Disease. J Lipid Res 6: 211–219.
- Miyatake T, Suzuki K (1972) Globoid cell leukodystrophy: additional deficiency of psychosine galactosidase. Biochem Biophys Res Commun 48: 539–543.
- Raghavan SS, Mumford RA, Kanfer JN (1973) Deficiency of glucosylsphingosine: beta-glucosidase in Gaucher disease. Biochem Biophys Res Commun 54: 256–263.
- Nilsson O, Mansson JE, Hakansson G, Svennerholm L (1982) The occurrence of psychosine and other glycolipids in spleen and liver from the three major types of Gaucher’s disease. Biochim Biophys Acta 712: 453–463.
- Nilsson O, Grabowski GA, Ludman MD, Desnick RJ, Svennerholm L (1985) Glycosphingolipid studies of visceral tissues and brain from type 1 Gaucher disease variants. Clin Genet 27: 443–450.
- Schueler UH, Kolter T, Kaneski CR, Blusztajn JK, Herkenham M, et al. (2003) Toxicity of glucosylsphingosine (glucopsychosine) to cultured neuronal cells: a model system for assessing neuronal damage in Gaucher disease type 2 and 3. Neurobiol Dis 14: 595–601.
- Orvisky E, Sidransky E, McKinney CE, Lamarca ME, Samimi R, et al. (2000) Glucosylsphingosine accumulation in mice and patients with type 2 Gaucher disease begins early in gestation. Pediatr Res 48: 233–237.
- Xu YH, Quinn B, Witte D, Grabowski GA (2003) Viable mouse models of acid beta-glucosidase deficiency: the defect in Gaucher disease. Am J Pathol 163: 2093–2101.
- Sun Y, Ran H, Zamzow M, Kitatani K, Skelton MR, et al. (2010) Specific saposin C deficiency: CNS impairment and acid beta-glucosidase effects in the mouse. Hum Mol Genet 19: 634–647.
- Sun Y, Liou B, Xu YH, Quinn B, Zhang WJ, et al. (2012) Ex Vivo and in Vivo Effects of Isofagomine on Acid beta-Glucosidase Variants and Substrate Levels in Gaucher Disease. Journal of Biological Chemistry 287: 4275–4287.
- Sun Y, Qi X, Grabowski GA (2003) Saposin C is required for normal resistance of acid beta-glucosidase to proteolytic degradation. J Biol Chem 278: 31918–31923.
- Sun Y, Quinn B, Witte DP, Grabowski GA (2005) Gaucher disease mouse models: point mutations at the acid {beta}-glucosidase locus combined with low-level prosaposin expression lead to disease variants. J Lipid Res 46: 2102–2113.
- Sun Y, Liou B, Ran H, Skelton MR, Williams MT, et al. (2010) Neuronopathic Gaucher disease in the mouse: viable combined selective saposin C deficiency and mutant glucocerebrosidase (V394L) mice with glucosylsphingosine and glucosylceramide accumulation and progressive neurological deficits. Hum Mol Genet 19: 1088–1097.
- Tybulewicz VLJ, Tremblay ML, LaMarca ME, Willemsen R, Stubblefield BK, et al. (1992) Animal model of Gaucher’s disease from targeted disruption of the mouse glucocerebrosidase gene. Nature 357: 407–410.
- Nilsson O, Hakansson G, Dreborg S, Groth CG, Svennerholm L (1982) Increased cerebroside concentration in plasma and erythrocytes in Gaucher disease: significant differences between type I and type III. Clin Genet 22: 274–279.
- Sandhoff K, Kolter T, Van Echten-Deckert G (1998) Sphingolipid metabolism. Sphingoid analogs, sphingolipid activator proteins, and the pathology of the cell. Ann N Y Acad Sci 845: 139–151.
- Michelin K, Wajner A, Bock H, Fachel A, Rosenberg R, et al. (2005) Biochemical properties of beta-glucosidase in leukocytes from patients and obligated heterozygotes for Gaucher disease carriers. Clin Chim Acta 362: 101–109.
- Ohashi T, Hong CM, Weiler S, Tomich JM, Aerts JM, et al. (1991) Characterization of human glucocerebrosidase from different mutant alleles. J Biol Chem 266: 3661–3667.
- Leonova T, Grabowski GA (2000) Fate and sorting of acid beta-glucosidase in transgenic mammalian cells. Mol Genet Metab 70: 281–294.
- Yamashita T, Wada R, Sasaki T, Deng C, Bierfreund U, et al. (1999) A vital role for glycosphingolipid synthesis during development and differentiation. Proc Natl Acad Sci U S A 96: 9142–9147.
- Saadat L, Dupree JL, Kilkus J, Han X, Traka M, et al. (2010) Absence of oligodendroglial glucosylceramide synthesis does not result in CNS myelin abnormalities or alter the dysmyelinating phenotype of CGT-deficient mice. Glia 58: 391–398.
- Jennemann R, Sandhoff R, Wang S, Kiss E, Gretz N, et al. (2005) Cell-specific deletion of glucosylceramide synthase in brain leads to severe neural defects after birth. Proc Natl Acad Sci U S A 102: 12459–12464.
- Orvisky E, Park JK, LaMarca ME, Ginns EI, Martin BM, et al. (2002) Glucosylsphingosine accumulation in tissues from patients with Gaucher disease: correlation with phenotype and genotype. Mol Genet Metab 76: 262–270.
- Gornati R, Berra B, Montorfano G, Martini C, Ciana G, et al. (2002) Glycolipid analysis of different tissues and cerebrospinal fluid in type II Gaucher disease. J Inherit Metab Dis 25: 47–55.
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