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I-cell disease-like phenotype in mice deficient in mannose 6-phosphate receptors
F Dittmer1, A Hafner, E J Ulbrich
1Georg-August-Universität Göttingen, Abt. Biochemie II, Germany.
Abstract:
Mannose 6-phosphate receptor deficient mice were generated by crossing mice carrying null alleles for Igf2 and the 300 kDa and 46 kDa mannose 6-phosphate receptors, Mpr300 and Mpr46. Pre- and perinatal lethality of mice nullizygous for Igf2, Mpr300 and Mpr46 was increased. Triple deficient mice surviving the first postnatal day had normal viability and developed a phenotype resembling human I-cell disease. The triple deficient mice were characterized by dwarfism, facial dysplasia, waddling gait, dysostosis multiplex, elevated lysosomal enzymes in serum and histological signs of lysosomal storage predominantly in fibroblasts, but also in parenchymal cells of brain and liver. A paternally inherited Mpr300 wild type allele that is normally inactive in mice due to imprinting was reactivated in some tissues of mice lacking IGF II and MPR 46 and carrying a maternal Mpr300 null allele. Inspite of the partial reactivation the phenotype of these mice was similar to that of triple deficient mice.
Insights
Mice lacking mannose 6-phosphate receptors (MPR300 and MPR46) and IGF II exhibit I-cell disease symptoms. Reactivation of a specific Mpr300 allele did not prevent this severe lysosomal storage disorder.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Mannose 6-phosphate receptors (M6PRs) are crucial for lysosomal enzyme trafficking.
- Insulin-like growth factor 2 (IGF-II) plays a role in embryonic development and growth.
- Deficiencies in M6PRs are linked to lysosomal storage disorders.
Purpose of the Study:
- To investigate the combined roles of M6PRs (MPR300, MPR46) and IGF-II in mouse development.
- To model human I-cell disease using genetically modified mice.
- To explore the impact of Mpr300 imprinting and reactivation in the absence of IGF-II and MPR46.
Main Methods:
- Generation of triple-deficient mice lacking Igf2, Mpr300, and Mpr46 alleles.
- Phenotypic analysis of resulting mice, including viability, growth, and specific disease markers.
- Investigation of Mpr300 imprinting and allele reactivation in specific tissues.
Main Results:
- Triple deficiency of Igf2, Mpr300, and Mpr46 led to increased pre- and perinatal lethality.
- Surviving triple-deficient mice displayed a phenotype consistent with human I-cell disease, including dwarfism and lysosomal storage.
- Partial reactivation of a paternally inherited Mpr300 allele in deficient mice did not rescue the disease phenotype.
Conclusions:
- Combined deficiency of M6PRs and IGF-II results in a severe lysosomal storage disorder resembling I-cell disease.
- Mpr300 imprinting and its reactivation patterns are influenced by the absence of IGF-II and MPR46.
- These findings highlight the critical interplay between M6PRs and IGF-II in development and lysosomal homeostasis.