Point mutation in the cytoplasmic domain of the neutrophil p22-phox cytochrome b subunit is associated with a nonfunctional NADPH oxidase and chronic granulomatous disease

Journal Article · Sun Dec 15 00:00:00 EST 1991 · Proceedings of the National Academy of Sciences of the United States of America; (United States)

DOI:https://doi.org/10.1073/pnas.88.24.11231· OSTI ID:5703806

Dinauer, M C ^[1]; Pierce, E A ^[2]; Erickson, R W; Curnutte, J T ^[3]; Muhlbeach, T J; Seger, R A ^[4]; Messner, H ^[5]; Orkin, S H ^[6]

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1. Indiana Univ., Indianapolis (United States)
2. Harvard Medical School, Boston, MA (United States)
3. Scripps Research Inst., La Jolla, CA (United States)
4. Univ. Children's Hospital, Zurich (Switzerland)
5. Children's Hospital, Klagenfurt (Austria)
6. Harvard Medical School, Boston, MA (United States) Howard Hughes Medical Inst., Boston, MA (United States)

Chronic granulomatous disease (CGD) is a congenital disorder in which phagocytes cannot generate superoxide (O{sub 2}{sup {minus}}) and other microbial oxidants due to mutations in any one of four components of the O{sub 2}{sup {minus}}-generating complex, NADPH oxidase. The authors report here a female CGD patient in whom a missense mutation in one of these components, the p22-phox subunit of the neutrophil membrane cytochrome b results in a nonfunctional oxidase and failure of neutrophils to produce O{sub 2}{sup {minus}} in response to phorbol 12-myristrate 13-acetate. Cytochrome b in the patient's neutrophils was normal in appearance and abundance as determined by visible spectroscopy and by immunoblots of the gp91 and p22 subunits. However, the neutrophil plasma membranes were devoid of activity in the cell-free oxidase activation system, whereas the cytosol functioned normally. They postulated that the patient was homozygous for a mutation in p22 that results in the synthesis of normal levels of nonfunctional cytochrome b. A single-base substitution (C {yields} A) was found in the patient's mononuclear cell p22-phox cDNA that predicts a nonconservative Pro {yields} Gln substitution at residue 156. These studies establish that this domain of p22-phox is cytoplasmic and that mutations in this region can have profound effects on cytochrome b function.

• OSTI ID: 5703806
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (United States), Vol. 88:24; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
CYTOCHROME OXIDASE
GENE MUTATIONS
CYTOCHROMES
ABSORPTION SPECTRA
HEREDITARY DISEASES
ETIOLOGY
AMINO ACID SEQUENCE
DNA BASE TRANSITIONS
NEUTROPHILS
PATIENTS
PHAGOCYTES
PHORBOL ESTERS
SUPEROXIDE DISMUTASE
ANIMAL CELLS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY FLUIDS
CARCINOGENS
DISEASES
ENZYMES
ESTERS
HAEM DEHYDROGENASES
LEUKOCYTES
MATERIALS
MOLECULAR STRUCTURE
MUTATIONS
ORGANIC COMPOUNDS
OXIDOREDUCTASES
PIGMENTS
PROTEINS
SOMATIC CELLS
SPECTRA
550200* - Biochemistry