遺伝学的スフィンゴ脂質活性化因子タンパク質欠損の分子的基礎

DOI
  • Suzuki Kunihiko
    Brain and Development Research Center, Department of Neurology and Psychiatry, University of North Carolina School of Medicine
  • 佐藤 いずみ
    東京工業大学・生命理工学部・生体分子工学科・糖鎖生命科学講座

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タイトル別名
  • Molecular Basis of Genetic Sphingolipid Activator Protein Deficiencies.

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A series of relatively small glycoproteins, normally localized in the lysosome, function as co-factors for physiological degradation of sphingoglycolipids with short hydrophilic head groups. Genetic deficiencies of the GM2 activator protein result in a clinical and biochemical phenotype essentially indistinguishable from the classical infantile form of Tay-Sachs disease. A single gene localized on human chromosome 5 codes for the GM2 activator protein. Genetic deficiencies of two homologous proteins, sap-B and sap-C, cause disorders resembling metachromatic leukodystrophy and Gaucher disease, respectively. Additional two putative activator proteins, sap-A and sap-D, are also known to activate degradation of some sphingolipids in vitro. However, the physiological significance of sap-A and sap-D in vivo has not been established. No disease state is known caused by specific genetic defects in either sap-A or sap-D. The four sap proteins are all homologous to each other and are generated by a single precursor translation product of the gene on chromosome 10, presumably by post-translational proteolytic processing. Recently, two patients have been identified in a single family in whom a mutation had occurred in the initiation codon of the sphingolipid activator gene. The patients' fibroblasts are totally deficient with the precursor protein and consequently with all four sphingolipid activator proteins. The patients showed a complex pathology and abnormal storage of several sphingolipids, suggesting that sap-A and sap-D also have in vivo activator functions but not necessarily on those lipids reported to be the substrates in in vitro experiments. For example, despite the in vitro activation of sphingomyelin degradation by three of the sap proteins (B, C, D), there was no abnormality in tissue sphingomyelin levels in these patients. These genetic disorders help clarifying the specificities of the individual sphingolipid activator proteins.

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