PMID- 10498624
OWN - NLM
STAT- MEDLINE
DCOM- 19991104
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 94
IP  - 7
DP  - 1999 Oct 1
TI  - Molecular characterization of autosomal recessive chronic granulomatous disease
      caused by a defect of the nicotinamide adenine dinucleotide phosphate (reduced
      form) oxidase component p67-phox.
PG  - 2505-14
AB  - Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocytes in
      which defective production of microbicidal oxidants leads to severe recurrent
      infections. CGD is caused by mutations in any of 4 genes encoding components of
      nicotinamide adenine dinucleotide phosphate (reduced form; NADPH) oxidase, the
      multisubunit enzyme that produces the precursor of these oxidants, superoxide.
      Approximately 5% of CGD patients have an autosomal recessive form of disease
      caused by a severe deficiency of p67-phox, a 526-amino acid subunit of the
      oxidase that appears to regulate electron transport within the enzyme. Here we
      report the biochemical and molecular characterization of 6 unrelated kindreds
      with p67-phox deficiency. These studies show that, as in gp91-phox and p22-phox
      deficiencies, the p67-phox CGD patients show a high degree of heterogeneity in
      the genetic defects that underlie their disease. Five different mutant alleles
      were identified: (1) a nonsense mutation in exon 4 (C(304) --> T); (2) a
      5-nucleotide (nt) deletion in exon 13 (nts 1169-1173); (3) a splice mutation in
      the first nucleotide of intron 4 (G --> A); (4) a deletion of 1 nt in exon 9
      (A(728)); and (5) a 9-nt in-frame deletion in exon 2 (nts 55-63). The splice
      mutation was seen in 3 unrelated kindreds, while the 5-nt deletion was seen in 2 
      apparently unrelated families (both of Palestinian origin). Homozygosity was
      present in 4 of the kindreds, 2 of which had consanguineous parentage. In the
      isolated neutrophils of each of the affected patients in the 6 kindreds, there
      was no measurable respiratory burst activity and no p67-phox protein detected by 
      immunoblot analysis. The level of 67-phox mRNA was less than 10% of normal in the
      mononuclear leukocytes from 3 of the 4 patients analyzed by Northern blot
      studies. Thus, this heterogeneous group of mutations in p67-phox all lead to
      marked instability of mRNA or protein (or both) that results in the complete loss
      of NADPH oxidase activity.
FAU - Patino, P J
AU  - Patino PJ
AD  - Department of Immunology, Genentech, Inc, South San Francisco, CA, USA.
FAU - Rae, J
AU  - Rae J
FAU - Noack, D
AU  - Noack D
FAU - Erickson, R
AU  - Erickson R
FAU - Ding, J
AU  - Ding J
FAU - de Olarte, D G
AU  - de Olarte DG
FAU - Curnutte, J T
AU  - Curnutte JT
LA  - eng
GR  - R01 AI24838/AI/NIAID NIH HHS/United States
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (DNA Primers)
RN  - 0 (Macromolecular Substances)
RN  - 0 (Phosphoproteins)
RN  - 0 (neutrophil cytosol factor 67K)
RN  - EC 1.6.3.- (NADPH Oxidases)
SB  - IM
MH  - Adolescent
MH  - Alleles
MH  - *Alternative Splicing
MH  - Base Sequence
MH  - Child
MH  - Child, Preschool
MH  - DNA Primers
MH  - Exons
MH  - Female
MH  - *Genes, Recessive
MH  - Granulomatous Disease, Chronic/blood/enzymology/*genetics
MH  - Humans
MH  - Macromolecular Substances
MH  - Male
MH  - *Mutation, Missense
MH  - NADPH Oxidases/deficiency/*genetics
MH  - Neutrophils/*enzymology
MH  - Nuclear Family
MH  - Phosphoproteins/*deficiency/*genetics
MH  - Polymerase Chain Reaction
MH  - *Sequence Deletion
EDAT- 1999/09/25 00:00
MHDA- 1999/09/25 00:01
CRDT- 1999/09/25 00:00
PHST- 1999/09/25 00:00 [pubmed]
PHST- 1999/09/25 00:01 [medline]
PHST- 1999/09/25 00:00 [entrez]
AID - S0006-4971(20)71134-1 [pii]
PST - ppublish
SO  - Blood. 1999 Oct 1;94(7):2505-14.