Molecular quality control machinery contributes to the leukocyte NADPH oxidase deficiency in chronic granulomatous disease

Shio Jean Lin, Ya Fang Huang, Jing Yi Chen, Paul G. Heyworth, Deborah Noack, Ji Yao Wang, Ching Yuan Lin, Bor Luen Chiang, Chin Mu Yang, Ching Chuan Liu, Chi Chang Shieh

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

Chronic granulomatous disease (CGD) is an inherited immunodeficiency disease caused by defects in leukocyte NADPH oxidase. Various inherited defects in one of the membrane-bound components of NADPH oxidase, gp91-phox, cause X-linked (X91) CGD. Analysis of three patients with X91 CGD revealed that different mechanisms of molecular quality control lead to the common phenotype of absence of mature membrane-bound NADPH oxidase complex in leukocytes. In the first patient, aberrant intron splicing created a premature stop codon. However, the mutant mRNA was degraded prematurely, which prevented the production of truncated protein. In the second patient, a frameshift mutation with the potential to generate a gp91-phox polypeptide, with an aberrant and elongated C-terminus, led to barely detectable levels of gp91-phox, even though the reported functional domains of the protein appeared unaffected. In the third patient, a point mutation created a single amino acid change in the predicted FAD-binding site of gp91-phox. Although gp91-phox was detectable with Western blotting, no cytochrome b558 was expressed on the cell surface. These analyses showed that molecular quality control machinery plays an important role in the pathogenesis of CGD, not only in the X910 but also in the X91- form of this X-linked disease.

Original languageEnglish
Pages (from-to)275-286
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1586
Issue number3
DOIs
Publication statusPublished - 2002 Apr 24

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology

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