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. Author manuscript; available in PMC: 2015 Sep 13.
Published in final edited form as: Blood Cells Mol Dis. 2010 Feb 18;44(4):291–299. doi: 10.1016/j.bcmd.2010.01.009

Hematologically Important Mutations: The Autosomal Recessive Forms of Chronic Granulomatous Disease (Second Update)

Dirk Roos 1, Douglas B Kuhns 2, Anne Maddalena 3, Jacinta Bustamante 4, Caroline Kannengiesser 5, Martin de Boer 1, Karin van Leeuwen 1, M Yavuz Köker 6, Baruch Wolach 7, Joachim Roesler 8, Harry L Malech 9, Steven M Holland 10, John I Gallin 9, Marie-José Stasia 11
PMCID: PMC4568122  NIHMSID: NIHMS182113  PMID: 20167518

Mutations in the genes encoding four of the phagocyte NADPH oxidase components, p22-phox, p47-phox, p67-phox and 40-phox, cause the autosomal recessive forms of chronic granulomatous disease (CGD). These four forms of the disease collectively account for approximately one-third of all CGD cases. Many new mutations have been identified in these four genes since publication of the first updated version of the tables with these mutations (1). The remaining two-thirds of cases are caused by mutations in the X-linked gene for gp91-phox, CYBB; these mutations have been tabulated previously in this journal (2). The incidence of CGD as a whole is between 1 in 200,000 and 1 in 250,000 individuals.

The protein p22-phox is one of two membrane-bound subunits of cytochrome b558 (the other is gp91-phox), and mutations in the p22-phox gene (CYBA, located at 16q24, OMIM *608508) account for about 6% of CGD (Table 1). Also about 6% of CGD cases are caused by mutations in the gene for p67-phox (NCF2, 1q25, OMIM *608515), a cytosolic component of the superoxide-generating NADPH oxidase system (Table 2). The most common form of autosomal recessive CGD (about 20% of all cases) is caused by mutations in the gene for p47-phox (NCF1, 7q11.23, OMIM *608512), a second cytosolic component of the enzyme (Table 3). Only one patient has been described with mutations in NCF4 (22q13.1, OMIM *601488), the gene encoding p40-phox, the third cytosolic NADPH oxidase component (Table 4). The type, position and number of the mutations in these four genes is depicted in figure 1. Tables 5-8 list apparently benign polymorphisms that have been identified in the CYBA, NCF2, NCF1 and NCF4 genes, respectively. It is important to realize that SNPs and other sequence variants available on the internet are not necessarily functionally neutral.

Table 1.

Mutations in the p22-phox gene CYBA.

Nucleotide change Mutation Amino acid or mRNA change CGD type Reference Families (alleles)a Accession number(s)g
g. del>10 kb Deletion NAb A22° [28] 1(2)
c.2T>A Missense p.Met1Lys A22? unpubl. d 1(2) c *
c.7C>T Nonsense p.Gln3X A22° [29] unpubl. 5(10) H0023
H0026
c.26G>A Nonsense p.Trp9X A22° [30] 1(1) H0017
c.27G>A Nonsense p.Trp9X A22° [31] 1(2) H0027
c.58+4_+7delAGTG e Splice site ins. 79 bp in intron 1
p.Ile20SerfsX77		 A22° [31,32] unpubl. 5(9) H0028
H0039
g.exon2_3del Deletion p.Ile20ArgfsX6 A22° [30] 1(2)
g.exon2_5del Deletion p.Ile20SerfsX68 A22° unpubl. 1(2) c *
c.70G>A Missense p.Gly24Arg A22° [16,29–31,33] unpubl. 9(14) H0021
H0024
H0025
H0028
H0030
H0034
c.71G>A Missense p.Gly24Glu A22° [16] 1(2) *
c.74G>T Missense p.Gly25Val A22° [30] 1(1) H0017
c.77delT Deletion p.Ile26ThrfsX48 A22° unpubl. 1(1) *
c.107G>A Nonsense p.Trp36X A22° [30] 1(1) H0021
g.exon3_5del Deletion p.Ile43MetfsX68 A22° [34] 1(2) *
g.exon3_6del Deletion NA A22° [33] 1(2) *
c.152T>A Missense p.Leu51Gln A22° unpubl. 1(1) *
c.155T>C Missense p.Leu52Pro A22° [30] 1(2) H0014
c.158A>T Missense p.Glu53Val A22° [35] 1(1) H0005
c.164C>G Missense p.Pro55Arg A22° [16] 1(2) *
c.166dupC Insertion p.Arg56ProfsX157 A22° [30,33] unpubl. 5(8) H0019
H0020
c.171delG Deletion p.Lys58ArgfsX16 A22° unpubl. 1(2) *
c.171dupG Insertion p.Lys58GlufsX155 A22° [16,35] unpubl. 5(9) H0005
H0032
H0036
H0037
c.173delA # Deletion p.Lys58ArgfsX16 A22° [34] 1(2) H0041 *
c.203+1G>T e Splice site del. exon 3
p.Ile43_Trp68delinsMet		 A22° [30] 1(2) H0016
c.204–2A>G e Splice site del. exon 4?
p.Gly69_Leu96del?		 A22° [36] 1(2) *
c.223delG # Deletion p.Ala75ProfsX3 A22° [34] 1(2) H0042 *
c.246delC Deletion p.Phe83LeufsX108 A22° [28,30] 2(3) H0001
H0015
c.261C>G Nonsense p.Tyr87X A22° unpubl. 1(2) *
c.261C>A Nonsense p.Tyr87X A22° unpubl. 1(2) *
c.268C>T Missense p.Arg90Trp A22° [30] unpubl. 8(14) H0018
H0019
H0020
c.268C>G Missense p.Arg90Gly A22° unpubl. 1(2) *
c.269G>A Missense p.Arg90Gln A22° [28,37] 2(3) H0001
H0006
H0007
H0008
c.269G>C Missense p.Arg90Pro A22° unpubl. 1(2) *
c.281A>G Missense p.His94Arg A22° [37] 1(2) H0012
c.287+1G>A e Splice site del. exon 4 p.Gly69_Leu96del A22° [37] unpubl. 2(4) H0009
H0035
c.287+1G>T e Splice site del. exon 4 p.Gly69_Leu96del A22° unpubl. 1(2) *
c.287+2T>C e Splice site del. exon 4?
p.Gly69_Leu96del?		 A22° unpubl. 1(1) f *
c.288–6_296del16 e Splice site del. exon5
p.Leu97ArgfsX68		 A22° unpubl. 1(1) *
c.288–15_308del36 e Splice site intron4ins179/exon5del21 A22° [38] 1(2) H0038 *
c.288G>T Splice site del. exon 5
p.Leu97ArgfsX68		 A22° unpubl. 1(2) *
c.295_301delGTGCCCG Deletion p.Val99ProfsX90 A22° [13,17,19] unpubl. 5(10) c H0040 *
c.339C>A Nonsense p.Cys113X A22° [33] 1(2) *
c.354C>A Missense p.Ser118Arg A22° [28,30] unpubl. 4(8) H0003
H0010
H0022
c.369+1G>C e Splice site del. exon 5
p.Leu97ArgfsX68		 A22° [6,39] 1(2) H0002
c.369+1G>A e Splice site del exon 5
p.Leu97ArgfsX68		 A22° [34] 1(2) H0045
H0046		 *
c.370G>T Missense p.Ala124Ser A22° [17] 1(2) *
c.371C>T Missense p.Ala124Val A22° [31] 1(1) H0030
c.373G>A Missense p.Ala125Thr A22° [34] 1(2) H0047 *
c.385G>A Missense p.Glu129Lys A22? unpubl. 1(2) *
c.385_388delGAGC Deletion p.Glu129SerfsX61 A22° [34] 2(4) H0043
H0044		 *
c.399delC Deletion p.Ile134SerfsX57 A22? unpubl. 1(2) c *
c.408delC Deletion p.Lys137SerfsX54 # A22° [33] 1(2) *
c.467C>A Missense p.Pro156Gln A22+ [40] 1(2) H0011
c.472_484del Deletion p.Pro160AlafsX27 A22? [1] 1(2) c H0031
c.571_604del Deletion p.Thr191ProfsX A22° [31] 1(2)
Mutations in CYBA
Number of different alleles Total number of alleles
Deletions 16 alleles (29.1%) 42 alleles (24.3%)
Nonsense mutations 7 alleles (12.7%) 20 alleles (11.6%)
Splice site mutations 11 alleles (20.0%) 29 alleles (16.8%)
Missense mutations 19 alleles (34.6%) 65 alleles (37.5%)
Insertions 2 alleles (3.6%) 17 alleles (9.8%)
Total 55 different allelic mutations Total 87 families with 173 identified alleles in the 96 patients
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a

Number of different families with patients with this mutation (number of alleles carrying this mutation).

b

Not applicable.

c

One patient presumed homozygous for this mutation.

d

Unpublished data from the authors' laboratories.

e

Position of introns in CYBA: intron 1 c.58_59; intron 2 c.128_129; intron 3 c.203_204; intron 4 c.287_288; intron 5 c.369_370.

f

Patient is heterozygous for this mutation and for an unidentified mutation in the other allele.

g

Accession number in database at http://www.uta.fi/imt/bioinfo/CYBAbase/.

*

New mutations since ref. [1].

#

Corrected after consultation of the authors.

Table 2.

Mutations in the p67-phox gene NCF-2.

Nucleotide change Mutation Amino acid or mRNA change CGD type Families (alleles) Reference Accession number h
c.–547–?_174+?del g Deletion p.Met1_Lys58del A67° 1(2) Unpubl. *
c–274–?_174 + ?del∼400 g Deletion p.Met1_Lys58del A67° 1(2) Unpubl. *
c–274–?_174 + ?del∼400 g Deletion p.Met1_Lys58del A67° 1(2) Unpubl. *
c.1A>G Missense p.Met1Val A67° 1(1) Unpubl. *
c.29G>A Nonsense p.Trp10X A67° 1(2) Unpubl. *
c.55_63delAAGAAGGAC a Deletion p.Lys19_Asp21del A67° 4(4) [41–43] unpubl. M0004
M0015
c.125A>G Missense p.Asn42Ser A67° 1(2) Unpubl. *
c.130G>C Missense p.Gly44Arg A67? 2(4) b [1,43]
c.130G>T Missense p.Gly44Cys A67° 1(2) Unpubl. *
c.172_174delAAG Deletion p.Lys58del A67+ 2(3) c [44,45] unpubl. M0009
c.175–1G>A g Splice site del. exon 3?
p.Ala59IlefsX2?		 A67° 1(2) Unpubl. *
c.196C>T Nonsense p.Arg66X A67° 3(5) [42]
c.229C>T Nonsense p.Arg77X A67° 4(7) [46], unpubl. *
c.230G>A Missense p.Arg77Gln A67° 3(3) [42], unpubl. M0016
c.233G>A Missense p.Gly78Glu A67° 1(2) [47] M0002
c.257+2T>C g Splice site del. exon3
p.Ala59IlefsX2		 A67° 2(4) [13,48] M0010
M0020
c.258–?_366 + ?del∼1100 g Deletion p.Tyr87CysfsX22 A67? 1(2) Unpubl. *
c.279C>G d Missense p.Asp93Glu A67° 4(8) [46], unpubl. *
c.287_289delAAG Deletion p.Glu96del A67− 1(2) Unpubl. *
c.298C>T Nonsense p.Gln100X A67° 5(5) [42], unpubl. M0016
c.304C>T Nonsense p.Arg102X A67° 6(11) b [16,41,46,48] unpubl. M0001
c.305G>C Missense p.Arg102Pro A67+? 1(1) Unpubl. *
c.323A>T Missense p.Asp108Val A67−? 1(2) [43] *
c.364_366+2delGAGGT g Splice site del. exon 4?
p.Tyr87CysfsX2?		 A67° 1(2) [17] *
c.366+1G>A g Splice site del. exon 3_4
p.Ala59_Glu122del		 A67° 8(12) [17,41–43] unpubl. M0011
M0018
c.366+1G>C e, g Splice site del. exon 4?
p.Tyr87CysfsX22?		 A67° 4(8) Unpubl. *
c.366+2401_502–527 del1380 g Deletion del. exon 5
p.Val123_Trp167del		 A67° 4(8) [50] *
c.383C>T Missense p.Ala128Val A67° 1(2) [42] M0013
c.398_399dupAG Insertion p.Lys134ArgfsX12 A67° 1(2) [51] M0006
c.409T>A Missense p.Trp137Arg A67− 1(2) Unpubl. *
c.419C>G Missense p.Ala140Asp A67° 1(1) Unpubl. *
c.[479A>T; 481A>G] Dbl. missense p.AspLys160_161
ValGlu		 A67° 1(1) f [52] M0012
c.482delA Deletion p.Lys161ArgfsX16 A67? 1(2) b Unpubl. *
c.488_501delTGGAGTGTGTCTGG g Deletion/splice site del.exon 5
p.Val123_Trp167del		 A67° 1(1) Unpubl. *
c.502–1G>T g Splice site del exon 6?
p.Lys168_Thr203del?		 A67° 1(2) Unpubl. *
c.505C>G Missense p.Gln169Glu A67? 1(2) Unpubl. *
c.550C>T Nonsense p.Arg184X A67? 1(2) Unpubl. *
c.551G>C Missense p.Arg184Pro A67° 1(2) Unpubl. *
c.576C>T Nonsense p.Gln192X A67? 1(2) b [53] *
c.586_588delAAG Deletion p.Lys196del A67+ 1(2) Unpubl. *
c.605C>T Missense p.Ala202Val A67− 2(4) [46] unpubl. *
c.714-? _924+?dup∼1100 g Insertion p.Glu309GlyfsX15 A67° 2(3) f [54] unpubl. *
c.714–1G>T g Splice site del. exon 9?
p.Ala239ArgfsX59?		 A67° 1(1) Unpubl. *
c.728delA Deletion p.Glu243GlyfsX28 A67° 1(1) [41] *
c.767_768dupAA Insertion p.Glu257LysfsX15 A67° 1(2) Unpubl. *
c.799_800delGT Deletion pVal267LeufsX8 A67° 1(2) [17] *
c.835_836delAC Deletion p.Thr279GlyfsX16 A67° 2(4) b [42] unpubl. M0017
c.855+1G>A g Splice site del. exon 8_9
p.Ala224_Gln285del		 A67° 1(2) [55] M0007
c.1026G>A g Splice site del. exon 12
p.Gln335SerfsX38		 A67° 2(2) [49] *
c.1034dupA Insertion p.Leu346AlafsX36 A67? 1(1) Unpubl. *
c.1099C>T Nonsense p.Gln367X A67? 1(2) b Unpubl. *
c.1171_1175delAAGCT Deletion p.Lys391GlufsX9 A67° 6(12) [16,19,41] M0005
c.1179–2A>T g Splice site del. exon 14?
p.Ser393ArgfsX54?		 A67° 1(2) Unpubl. *
c.1256A>T Missense p.Asn419Ile A67° 1(2) [13] M0019 *
Mutations in NCF2
Number of different alleles Total number of alleles
Deletions 14 alleles (25.9%) 48 alleles (28.1%)
Nonsense mutations 8 alleles (14.8%) 36 alleles (21.0%)
Splice site mutations 11 alleles (20.4%) 38 alleles (22.2%)
Missense mutations 17 alleles (31.5%) 41 alleles (24.0%)
Insertions 4 alleles (7.4%) 8 alleles (4.7%)
Total 54 different allelic mutations Total 83 families with 171 identified alleles in the 95 patients
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a

Always in combination with c.1183C>T (polymorphism, rs13306575) on the same allele.

b

One patient presumed homozygous for this mutation.

c

One patient is heterozygous for this mutation and for an undefined deletion of 11-13 kb in the other allele [44,45].

d

Always in combination with c.366+1G>C on the same allele.

e

Always in combination with c.279C>G on the same allele.

f

One patient is heterozygous for this mutation and for an unidentified mutation in the other allele [54].

g

Positions of introns in NCF2: intron 1 c.–510_–274 in 5′ UTR; intron 2 c.174_175; intron 3 c.257_258; intron 4 c.366_367; intron 5 c.501_502; intron 6 c.609_610; intron 7 c.669_670; intron 8 c.713_714; intron 9 c.855_856; intron 10 c.924_925; intron 11 c.1000_1001; intron 12 c.1026_1027; intron 13 c.1178_1179; intron 14 c.1290_1291; intron 15 c.1468_1469.

h

Accession number in database at http://www.uta.fi/imt/bioinfo/NCF2base/.

Table 3.

Mutations in the p47-phox gene NCF1.

Nucleotide change Mutation Amino acid or mRNA change CGD type Families (alleles) Reference Accession number(s) a
c.72+1G>A e Splice site del. exon 1?
p.Met1_Tyr24del?		 A47° 1(1) [8] N0031
c.72+3G>T e Splice site del. exon 1?
p.Met1_Tyr24del?		 A47° 1(1)] [8 N0032
c.75_76delGT Deletion p.Tyr26HisfsX26 A47° >300 homozygous, 20 heterozygous b [3–19] unpubl. N0004–7,9–23, 27–29, 31–35, 40–63, 69,70
c.125G>A Missense p.Arg42Gln A47° 3(3) [8] unpubl. N0034N0035
c.153+1G>A e Splice site c.153+1_+73insc
p.Lys52MetX24		 A47° 1(1) [14] N0068 *
c.154–283_451+821 del2858 e Deletion del. exon 3_5
p.Lys52ThrfsX82		 A47° 1(1) [14] N0061 *
c.271C>T Nonsense p.Gln91X A47° 1(1) [14] N0027 *
c.333T>A Nonsense p.Cys111X A47° 1(1) [9,14] N0028
N0056
N0057
N0058
c.353_354delCC insAA Deletion/insertion p.Phe118X A47° 1(1) [10,14] N0059 *
c.417_451+650 del685 e Deletion del. exon 5
p.Thr133HisfsX66		 A47° 1(1) unpubl. *
c.502delG Deletion p.Glu168ArgfsX19 A47° 1(1) [5] N0002
c.574G>A e Splice site del. exon 6+7 d
p.Asp151_Ala227del		 A47° 4(7) unpubl. [8, 14] N0036
N0064
N0065
N0066
N0067
c.579G>A Nonsense p.Trp193X A47° 17(31) [14,16,56] unpubl. N0024
N0025
N0026
N0037
N0038
N0039
N0060
N0068		 *
c.604C>T Nonsense p.Arg202X A47° 1(1) [17] *
c.612G>A Nonsense p.Trp204X A47? 1(2) f [57] *
c.678T≫G Nonsense p.Tyr226X A47° 1(2) [17] *
c.682+1G>C e Splice site del. exon 7
p.Trp193_Gly228del		 A47° 1(1) [14] N0062
N0063		 *
c.730G>A Missense p.Glu244Lys A47° 1(1) unpubl. *
c.734_748del15 Deletion p.Val245_Glu249del A47° 1(2) unpubl. *
c.784G>A Missense p.Gly262Ser A47° 1(1) [8] N0033
c.789G>C Missense p.Trp263Cys A47° 1(1) unpubl. *
c.811delG Deletion p.Val271SerfsX105 A47° 1(1) [8]
c.838delC Deletion p.Leu280CysfsX96 A47° 1(1) [18] *
Mutations in NCF1
Number of different alleles Total number of alleles
Deletions 7 alleles (30.4%) 7 alleles (11.1%)
Nonsense mutations 6 alleles (26.1%) 38 alleles (60.3%)
Splice site mutations 5 alleles (21.7%) 11 alleles (17.5%)
Missense mutations 4 alleles (17.4%) 6 alleles (9.5%)
Deletion/insertions 1 allele (4.4%) 1 allele (1.6%)
Total 23 different allelic mutations (including delta-GT) Total 42 families with 6 (other than delta-GT) in 3 identified alleles the 53 patients
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a

Accession number in database at http://www.uta.fi/imt/bioinfo/NCF1base/.

b

One patient is a compound heterozygote for this mutation and for an undefined chromosomal microdeletion on the other allele [58].

c

Activation of cryptic donor splice site in intron 2, leading to incorporation of 73 nucleotides from the 5′ side of intron 2 into mRNA, including the mutated G>A at position +1 of intron 2. At the protein level, this mutation predicts incorporation of 24 aberrant amino acids after His51, followed by a stop codon at position 76 [14].

d

In addition, these patients show evidence of mRNA for p47phox from which the last 22 bp at the 3′ region of exon 6 has been skipped (r.552_574del), as well as mRNA in which intron 6 has been included and in which the mutated exon 6 is expressed (r.[intron6+1_exon6–1ins; 574 g>a]) [14].

e

Positions of introns in NCF1: intron 1 c.72_73; intron 2 c.153_154; intron 3 c. 229_230; intron 4 c.395_396; intron 5 c.451_452; intron 6 c.574_575; intron 7 c.682_683; intron 8 c.801_802; intron 9 c.905_906; intron 10 c.1051_1052.

f

Patient presumed to be homozygous for the mutation.

Table 4.

Mutations in the p40-phox gene NCF4.

Nucleotide change Mutation Amino acid or mRNA change CGD type Families (alleles) Reference
c.143_152dup10 Insertion p.Lys52ArgfsX79 A40° 1(1) [59] *
c.314G>A Missense p.Arg105Gln A40+ 1(1) [59] *
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Figure 1. Schematic overview of mutations in NCF2, CYBA, NCF4 and NCF1.

Figure 1

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For each cDNA, the exon positions and the corresponding protein domains have been depicted. For some of the protein domains, their interaction with other proteins has been indicated. The PX domains interact with phosphatidyl-inositol-phosphates. The type of mutations (explained in the right hand corner), their position and number of mutated alleles are indicated. Splice site mutations are given at the exon borders.

Table 5.

Polymorphisms in the p22-phox gene CYBA.

Polymorphic nucleotide Amino acid change Reference
c.59–37A/G NA [30]
c.36A/G p.Glu12Glu [60]
c.179A/C p.Lys60Thr [30]
c.214C/T p.His72Tyr [28,60]
c.288–138ins50 NA [13]
c.381T/C p.Arg127Arg [60]
c.403G/A p.Glu135Lys [30]
c.480G/A p.Pro160Pro [30,37,60]
c.512A/G p.Glu171Gly [60]
c.521C/T p.Ala174Val [28,30,31,60]
c.579G/T p.Glu193Asp [60]
c.612A/G (+24 of 3′ UT region) NA [37,60]
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Table 8.

Polymorphisms in the p40-phox gene NCF4.

Polymorphic nucleotidea Amino acid change Reference
c.32+1258G/T N.A. [61]
c.33–1101T/C N.A. [61]
c.33–728T/C N.A. [61]
c.118–360G/A N.A. [61]
c.342+202G/C N.A. [61]
c.342+342G/T N.A. [61]
c.342+1326G/A N.A. [61]
c.343–1378A/G N.A. [61]
c.343–339A/G N.A. [61]
c.528+16G/A N.A. [61]
c.627+711G/A N.A. [61]
c.627+1040G/T N.A. [61]
c.628–1193G/A N.A. [61]
c.758+57A/T N.A. [61]
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a

Positions of introns in NCF4: intron 1 c.32_33; intron 2 c.117_118; intron 3 c.271_272; intron 4 c.342_343; intron 5 c.470_471; intron 6 c.528_529; intron 7 c.627_628; intron 8 c.758_759; intron 9 c.824_825.

Unlike the other autosomal recessive and X-linked forms of the disease, in which there is a large heterogeneity among mutations, a single defect accounts for the vast majority of cases of p47-phox-deficiency. Of ∼250 patients investigated worldwide at the DNA level, all but 53 patients in 42 families appear to be homozygous for a dinucleotide (GT) deletion (ΔGT) at the start of exon 2 (3-19). Of the 42 families with exceptions, 20 had patients who were compound heterozygotes for the GT deletion and one additional mutation, and the others had patients with mutations other than ΔGT on both alleles of NCF1 (20 homozygous, 2 compound heterozygous). The ΔGT-bearing allele of NCF1 is therefore the most common CGD-causing allele in the population, carried by approximately 1 in 250 individuals. The reason for this predominance is that most normal individuals have two p47-phox pseudogenes, each of which co-localizes with the functional gene to 7q11.23 and carries ΔGT. Recombination events between NCF1 and these highly homologous pseudogenes lead to the incorporation of ΔGT into NCF1 (7, 20).

Additional information about the tabulated mutations and about CGD in general can be found in recent reviews (21-25) and in the cited literature. In the following tables we have used the standard notation for differentiating the various phenotypes of CGD (e.g., A22°, A22+, A67°, A67+, A67 −, A47°, A40° and A40+). In this nomenclature the first letter refers to the mode of inheritance (autosomal recessive), the numeral indicates the phox component affected, and the superscript symbol indicates whether the protein is absent (°), diminished (−) or normal (+), based on immunoblot analysis. When this information is unavailable, that has been indicated as (?). The respective proteins can be non-functional, exert residual activity, or in case of (−) be fully functional. Online Mendelian Inheritance in Man (OMIM) numbers for A22, A67, A47 CGD are #233690, #233710, and #233700, respectively. Mutations added since the last updated versions of Tables 1-3 were published (1) are marked with an asterisk in the right hand column. The nucleotide numbering system we have used is based on the cDNA sequence and follows the convention that +1 is the A of the ATG initiator codon. This differs from the numbering of the GenBank sequences; for p22-phox (GenBank accession nos. M21186 and J03774) subtract 28 from the GenBank sequence number to make the initiator A +1; for p67-phox (accession no. M32011) subtract 67 from the GenBank numbering; for p47-phox (GenBank accession nos. M25665 and M26193) subtract 12 from the GenBank numbering, and for p40-phox (accession no. NM_000631) subtract 184 from the GenBank numbering. The notation of the mutations and polymorphisms follows the recommendations of the Human Genome Variation Society (26) (see also www.hgvs.org/mutnomen). Where possible we have cross-referenced the mutations listed here with those in three CGD databases that list CGD patients by accession number. These databases contain additional biochemical, genetic and clinical information and are available at http://www.uta.fi/imt/bioinfo/CYBAbase/ (or NCF1base/, or NCF2base/). In addition, information can also be found in the HGMD database at http://www.hgdm.cf.ac.uk/ac.search.php. The consequences of the mutations for protein composition have been checked with the Mutalyzer program (www.lovd.nl/mutalyzer) (27).

Table 6.

Polymorphisms in the p67-phox gene NCF2.

Polymorphic nucleotide Amino acid change Reference
c.–185G/A NA [41,42]
c.–181G/A NA [41,42]
c.–24C/T NA [41,42]
c.235A/G p.Met79Val [41]
c.542A/G p.Lys181Arg [41,42,51]
c.606G/A p.Ala202Ala [42]
c.895C/T p.Leu299Leu [41,47,51]
c.925–21G/A NA [41]
c.983G/A p.Arg328Lys [41,47,51]
c.1105G/A p.Gly369Arg [42]
c.1167C/A p.His389Gln [41,42]
c.1183C/T p.Arg395Trp [41–43]
Open in a new tab

Table 7.

Polymorphisms in the p47-phox gene NCF1.

Polymorphic nucleotidea Amino acid change Reference
c.66G/C p.Glu22His Unpubl.
c.73G/A p.Val25Met Unpubl.
c.345C/T p.Leu115Leu [8]
c.468C/T p.Ile156Ile Unpubl.
c.558A/G p.Val186Val Unpubl.
c.621G/A p.Ala206Ala Unpubl.
c.825C/T p.Phe275Phe Unpubl.
c.849A/G p.Ser283Ser Unpubl.
c.936C/T p.His312His Unpubl.
Open in a new tab
a

Identification of polymorphic sites in NCF1 is complicated by the p47-phox pseudogenes, which contain several differences from the functional gene; the referenced polymorphism was identified after amplification of NCF1 with primers that do not bind to the pseudogenes [8]. More synonymous polymorphisms can be expected to be introduced into NCF1 by recombination with the pseudogenes [20].

Acknowledgments

We thank the CGD Research Trust, London, UK, for financial support. We thank Katrin Höhne (Univ. Children's Hospital, Dresden, Germany), for excellent assistance. We are grateful to Cécile Martel, Michelle Mollin and Sylvain Beaumel for their constant and excellent technical assistance and we sincerely thank all the physicians collaborating with and trusting in the CGD diagnosis and research Center in Grenoble, France.

This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Footnotes

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