H. Nunoi et al., AG DINUCLEOTIDE INSERTION IN A PATIENT WITH CHRONIC GRANULOMATOUS-DISEASE LACKING CYTOSOLIC 67-KD PROTEIN, Blood, 86(1), 1995, pp. 329-333
The 67-kD cytosolic protein (p67-phox) is an essential component of th
e superoxide-generating system in phagocytes, and its defect is known
to cause chronic granulomatous disease (CGD). We sequenced p67-phox cD
NA from one of seven patients found in Japan and his parents. In the p
atient's cDNA, homozygous AG dinucleotide insertion at position 399 (o
r 401) was found together with three other homozygous substitutions in
a coding region (A-542 to G, T-895 to C and A-983 to G) compared with
the sequence reported for HL-60 cells. In cDNA from his parents, the
AG insertion was found to be heterozygous. In contrast, the other thre
e substitutions were found homozygously in his father's specimen and t
he latter two in his mother's specimen. The substitution of A-542 to G
was heterozygous in his mother's cDNA. The AG insertion would induce
a frame shift and bring about a stop codon at the position of 433. How
ever, the other three differences would give insignificant changes for
the protein function, if any, because the substitutions of A-542 to G
and A-983 to G result in the conservative amino acid transitions, ie,
Lys-180 to Arg and Lys-327 to Arg, and that of T-895 to C no amino ac
id change. Neutrophils from the patients completely lacked superoxide
generating activity whereas those from his parents generated substanti
al amounts of superoxide anion upon stimulation. Thus, it is concluded
that the AG dinucleotide insertion is responsible for the disease in
this patient. (C) 1995 by The American Society of Hematology.