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Molecular pathogenesis of human CD59 deficiency.

ABSTRACT: Objective:To characterize all 4 mutations described for CD59 congenital deficiency. Methods:The 4 mutations, p.Cys64Tyr, p.Asp24Val, p.Asp24Valfs*, and p.Ala16Alafs*, were described in 13 individuals with CD59 malfunction. All 13 presented with recurrent Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy, recurrent strokes, and chronic hemolysis. Here, we track the molecular consequences of the 4 mutations and their effects on CD59 expression, localization, glycosylation, degradation, secretion, and function. Mutants were cloned and inserted into plasmids to analyze their expression, localization, and functionality. Results:Immunolabeling of myc-tagged wild-type (WT) and mutant CD59 proteins revealed cell surface expression of p.Cys64Tyr and p.Asp24Val detected with the myc antibody, but no labeling by anti-CD59 antibodies. In contrast, frameshift mutants p.Asp24Valfs* and p.Ala16Alafs* were detected only intracellularly and did not reach the cell surface. Western blot analysis showed normal glycosylation but mutant-specific secretion patterns. All mutants significantly increased MAC-dependent cell lysis compared with WT. In contrast to CD59 knockout mice previously used to characterize phenotypic effects of CD59 perturbation, all 4 hCD59 mutations generate CD59 proteins that are expressed and may function intracellularly (4) or on the cell membrane (2). None of the 4 CD59 mutants are detected by known anti-CD59 antibodies, including the 2 variants present on the cell membrane. None of the 4 inhibits membrane attack complex (MAC) formation. Conclusions:All 4 mutants generate nonfunctional CD59, 2 are expressed as cell surface proteins that may function in non-MAC-related interactions and 2 are expressed only intracellularly. Distinct secretion of soluble CD59 may have also a role in disease pathogenesis.

SUBMITTER: Karbian N

PROVIDER: S-EPMC6244018 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Molecular pathogenesis of human CD59 deficiency.

Karbian Netanel N Eshed-Eisenbach Yael Y Tabib Adi A Hoizman Hila H Morgan B Paul BP Schueler-Furman Ora O Peles Elior E Mevorach Dror D

Neurology. Genetics 20181026 6

<h4>Objective</h4>To characterize all 4 mutations described for CD59 congenital deficiency.<h4>Methods</h4>The 4 mutations, p.Cys64Tyr, p.Asp24Val, p.Asp24Valfs*, and p.Ala16Alafs*, were described in 13 individuals with CD59 malfunction. All 13 presented with recurrent Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy, recurrent strokes, and chronic hemolysis. Here, we track the molecular consequences of the 4 mutations and their effects on CD59 expression, localizatio ...[more]

PMID: 30533526

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Molecular pathogenesis of human CD59 deficiency.

Publications

Molecular pathogenesis of human CD59 deficiency.

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