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Citing this page:
Lefranc, M.-P. and Lefranc, G. Human Gm, Km and Am allotypes and their molecular characterization: a remarkable demonstration of polymorphism In: B. Tait, F. Christiansen (Eds.), Immunogenetics, chap. 34, Humana Press, Springer, New York, USA. Methods Mol. Biol. 2012; 882, 635-680. PMID: 22665258, LIGM: 406

G1m allotypes

Description of the G1m allotypes

On the immunoglobulin heavy gamma 1 chains (H-gamma1), the following serological markers have been characterized [6]:
four G1m allotypes: G1m17, G1m3, G1m1 and G1m2,
two G1m alloallotypes: G1m27 and G1m28 (first characterized and defined as G3m allotypes),
and two G1m isoallotypes: nG1m17 and nG1m1.

The G1m allotypes and alloallotypes define seven G1m alleles [6] which correspond to nine potential IGHG1 alleles (Table below).

G1m17, G1m3 and nG1m17

The allotype G1m17 or G1m(z) corresponds to IGHG1 CH1 [Lys(K)120, a359] according to the IMGT unique numbering for C-DOMAIN [1] (Exon numbering 97 [2], Eu numbering 214 [3]).
The allotype G1m17 (CH1 K120) (pale blue in the Table) is found on alleles IGHG1*01, IGHG1*02, IGHG1*04, IGHG1*05, IGHG1*05p, IGHG1*06p and IGHG1*07p [2,4,5,6].

The allotype G1m3 or G1m(f) corresponds to IGHG1 CH1 [Arg(R)120, g359]. For its expression, G1m3 is dependent on the presence of the IGHG1 CH1 isoleucine I103 [6].
The allotype G1m3 (R120 and I103) (blue in the Table) is found on alleles IGHG1*03 (G1m3 and nG1m1) and IGHG1*08p (G1m3,1) [4,5,6].

The Arg(R)120 is also found on IGHG3 and IGHG4 and is responsible of the isoallotype nG1m17 or nG1m(z) present on IGHG1 nG1m17 (IGHG1*03 G1m3 and IGHG1*08p G1m3,1), IGHG3 and IGHG4 [5,6].

G1m1 and nG1m1

The allotype G1m1 or G1m(a) corresponds to IGHG1 CH3 [Asp(D)12, t36; Leu(L)14, c40] according to the IMGT unique numbering for C-DOMAIN [1] (Exon numbering 16 and 18 [2], Eu numbering 356 and 358 [3]).
The allotype G1m1 (CH3 D12, L14) (pale yellow in the Table) is found on alleles IGHG1*01, IGHG1*02, IGHG1*04, IGHG1*05, IGHG1*05p IGHG1*06p, IGHG1*07p and IGHG1*08p [4,5,6].

The isoallotype nG1m1 or nG1m(a) corresponds to IGHG1 CH3 [Glu(E)12, g36; Met(M)14, a40].
The isoallotype nG1m1 (CH3 E12, M14) is found on allele IGHG1*03 [2,4,5,6] and on IGHG2, IGHG3 and IGHG4 (only detected on H-gamma4 by certain antisera [6]).

G1m2

The allotype G1m2 or G1m(x) corresponds to IGHG1 CH3 [Gly(G)110, g329] according to the IMGT unique numbering for C-DOMAIN [1] (Exon numbering 91, Eu numbering 431 [3]).
The allotype G1m2 (purple in the Table) is found on allele IGHG1*07p (G. Lefranc and M.-P. Lefranc, personal communication and [6]).

The absence of the allotype G1m2 corresponds to IGHG1 CH3 [Ala(A)110, c329] which is found on alleles IGHG1*01, IGHG1*02, IGHG1*03, IGHG1*04, IGHG1*05, IGHG1*05p, IGHG1*06p and IGHG1*08p [4,5,6] and on IGHG2, IGHG3 and IGHG4. Ala(A)110 is not an isoallotype as no antibody reagent has been characterized [6].

G1m27 and G1m28

Both Gm27 and Gm28 are qualified as "alloallotype", being an allotype for two different gamma chains, gamma1 (G1m27, G1m28) and gamma3 (G3m27, G3m28), depending on the populations [6].

The allotype G1m27 corresponds to IGHG1 CH3 [Ile(I)101, a301] according to the IMGT unique numbering for C-DOMAIN [1] (Exon numbering 82, Eu numbering 422 [3]).
The allotype G1m27 (green in the Table) is found on alleles IGHG1*04 and IGHG1*06p [6].

The allotype G1m28 corresponds to IGHG1 CH3 [Arg(R)115, g344; Tyr(Y)116] according to the IMGT unique numbering for C-DOMAIN [1] (Exon numbering 95 and 96, Eu numbering 435 and 436 [3]).
The allotype G1m28 (yellow in the Table) is found on alleles IGHG1*05p and IGHG1*06p [6].

IGHG1*01, IGHG1*02 and IGHG1*05 are G1m17,1 (previously written G1m1,17).
IGHG1*03 is G1m3 (previously written Gm3).
IGHG1*04 is G1m17,1,27 (1).
IGHG1*05p is G1m17,1,28.
IGHG1*06p is G1m17,1,27,28.
IGHG1*07p is G1m17,1,2 (previously written G1m1, 2, 17).
IGHG1*08p is G1m3,1.

G1m allotypes on Homo sapiens gamma1 chains

G1m1_G1m2 allotypes
Fig. 1. G1m allotypes localizations on Homo sapiens IG gamma1 chains [6].

The CH1, CH2 and CH3 of the b12 gamma1 chains are shown (IMGT/3Dstructure-DB, code PDB:1hzh), with the positions involved in the G1m allotypes [6].
The CH2 position 45.1 is not related to the G1m allotypes, but indicates the amino acid position that should be responsible of the G2m23 allotype, or of its absence (G2m..), on a gamma2 chain [6].

G1m17_G1m3 allotypes
Fig. 2. G1m17, G1m3 allotypes and nG1m17 on the CH1 of the Homo sapiens IG gamma1 chains [6]

Three-dimensional structure of the IGHG1 CH1. The CH1 domain is from the b12 antibody (IMGT/3Dstructure-DB, code PDB:1hzh).
The lysine K120 (strand G) and the isoleucine I103 (strand F) are shown [6]. The K120 corresponds to the G1m17 allotype. The simultaneous presence of I103 (specific of the gamma1 isotype) and of arginine R120 would correspond to the G1m3 allotype.
The R120 would correspond to the nG1m17 isoallotype [6].

G1m1_nG1m1 allotypes
Fig. 3. G1m1 allotype and nG1m1, G1m2 allotype on the CH3 of the Homo sapiens IG gamma1 chains [6].

Three-dimensional structure of the IGHG1 CH3. The CH3 domain is from the b12 antibody (IMGT/3Dstructure-DB, code PDB:1hzh). Positions 12 and 14 of the G1m1/nG1m1 allotype, and position 110 of the G1m2/- allotype in the IGHG1 CH3 domain are shown [6].
The aspartate D12 and leucine L14 correspond to the G1m1 allotype, whereas alanine A110 corresponds to the absence of the G1m2 allotype. Glutamate E12 and and methionine M14 would correspond to nG1m1, whereas a glycine G110 would correspond to G1m2 [6].

Reference to be quoted for the three Figures G1m allotypes:
Lefranc, M.-P. and Lefranc, G., Methods Mol. Biol. 2012; 882, 635-680. PMID: 22665258 LIGM: 406 [6]

Correspondence between G1m alleles, IGHG1 allele names and sequence polymorphisms

Amino acid positions (2)
CH1 CH3
G1m
alleles
 
IGHG1
allele names
(nt)
120 12 14 101 110 115 116
(97) (16) (18) (82) (91) (95) (96)
214 356 358 422 431 435 436
G1m17,1 IGHG1*01
IGHG1*02
IGHG1*05
K120
(G1m17)
D12, L14
(G1m1)
K
Lys
aaa
D
Asp
gat
L
Leu
ctg
V
Val
gtc
A
Ala
gct
H
His
cac
Y
Tyr
tac
G1m3 IGHG1*03 R120 with I103
(G1m3)
R120
(nG1m17)
E12, M14
(nG1m1)
R
Arg
aga
E
Glu
gag
M
Met
atg
V
Val
gtc
A
Ala
gct
H
His
cac
Y
Tyr
tac
G1m17,1,27 IGHG1*04 (1) K120
(G1m17)
D12, L14
(G1m1)
I101
(G1m27)
K
Lys
aaa
D
Asp
gat
L
Leu
ctg
I
Ile
atc
A
Ala
gct
H
His
cac
Y
Tyr
tac
G1m17,1,28 IGHG1*05p (3) K120
(G1m17)
D12, L14
(G1m1)
R115, Y116
(G1m28)
K
(Lys)
aaa
D
(Asp)
gat
L
(Leu)
ctg
V
Val
gtc
A
(Ala)
gct
R
(Arg)
(cgc)
Y
Tyr
tac
G1m17,1,27,28 IGHG1*06p (3) K120
(G1m17)
D12, L14
(G1m1)
I101
(G1m27)
R115, Y116
(G1m28)
K
(Lys)
aaa
D
(Asp)
gat
L
(Leu)
ctg
I
(Ile)
atc
A
(Ala)
gct
R
(Arg)
cgc
Y
(Tyr)
tac
G1m17,1,2 IGHG1*07p (3) K120
(G1m17)
D12, L14
(G1m1)
G110
(G1m2)
K
(Lys)
(aaa)
D
(Asp)
(gat)
L
(Leu)
(ctg)
V
Val
gtc
G
Gly
(ggt)
H
His
(cac)
T
Tyr
(tac)
G1m3,1 IGHG1*08p (3) R120 with I103
(G1m3)
R120
(nG1m17)
D12, L14
(G1m1)
R
(Arg)
aga
D
(Asp)
(gat)
L
(Leu)
(ctg)
V
Val
gtc
A
(Ala)
(gct)
H
His
(cac)
Y
(Tyr)
(tac)

IMGT notes:
(1) IGHG1*04 differs from the alleles IGHG1*01, IGHG1*02 and IGHG1*05 by the amino acid change V101>I which corresponds to the allotype Gm27 [6], IGHG1*04 is therefore G1m17,1,27.
(2) Amino acid numbering in bold is according to IMGT unique numbering for C-DOMAIN [1], between parentheses: exon numbering [2] and in italics: Eu numbering [3].
(3) IGHG1*05p, IGHG1*06p, IGHG1*07p and IGHG1*08p amino acid and codon between parentheses are expected (G. Lefranc and M.-P. Lefranc) [2,5,6] but not yet sequenced at the nucleotide level and therefore the IGHG1*05p, IGHG1*06p, IGHG1*07p and IGHG1*08p alleles are not shown in Alignments of alleles: IGHG1. The alleles IGHG1*05p (G1m17,1,28), IGHG1*06p (G1m17,1,27,28), IGHG1*07p (G1m17,1,2) and IGHG1*08p (G1m3,1), described in Lefranc and Lefranc [6] (Table 4, p649), will be assigned with a definitive allele number (based on a chronological basis, and therefore unrelated to the provisional 'p' number) when a complete genomic sequence will be available.
IMGT references:
[1] Lefranc, M.-P. et al., Dev. Comp. Immunol., 29, 185-203 (2005). PMID: 15572068 pdf with permission from Elsevier
[2] Lefranc G. and Lefranc M.-P. The Immunoglobulin FactsBook, Academic press, London, UK, 458 pages (2001).
[3] Correspondence between C numberings (in IMGT Scientific chart).
[4] Alignment of alleles: Human IGHG1 (in IMGT Repertoire).
[5] Lefranc G. PhD Thesis. Allotypes et haplotypes des immunoglobulines dans les communautés libanaises: intérêt exceptionnel en immunogénétique et séro-anthropologie (in French). Immunoglobulin allotypes and haplotypes in the Lebanese communities : discussion of unusual genetic events and population structure (in English) Université de Rouen (1978).
[6] Lefranc, M.-P. and Lefranc, G. Human Gm, Km and Am allotypes and their molecular characterization: a remarkable demonstration of polymorphism In: B. Tait, F. Christiansen (Eds.), Immunogenetics, chap. 34, Humana Press, Springer, New York, USA. Methods Mol. Biol. 2012; 882, 635-680. PMID: 22665258, LIGM: 406

IGHG1 alleles and G1m allotypes (in populations for antibody engineering)

Excerpt of:

Lefranc M-P. IMGT® immunoglobulin repertoire analysis and antibody humanization.

In: Alt, F.W, Honjo, T, Radbruch A. and Reth, M. (Eds.), Molecular Biology of B cells, Second edition, Academic Press, Elsevier Ltd, London, UK, Chapter 26, 2014, PP. 481-514. dx.doi.org, ISBN : 978-0-12-397933-9. LIGM: 438
page 508-509 (source above to be quoted)

Allotypes are polymorphic markers of an IG subclass that correspond to amino acid changes and are detected serologically by antibody reagents (74). In therapeutic antibodies (human, humanized or chimeric) (11), allotypes may represent potential immunogenic residues (73), as demonstrated by the presence of antibodies in individuals immunized against these allotypes (74). The allotypes of the human heavy gamma chains of the IgG are designated as Gm (for gamma marker). The allotypes G1m, G2m and G3m are carried by the constant region of the gamma1, gamma2 and gamma3 chains, encoded by the IGHG1, IGHG2 and IGHG3 genes, respectively (74). The gamma1 chains may express four G1m alleles (combinations of G1m allotypes): G1m3, G1m3,1, G1m17,1, and G1m17,1,2 (and in Negroid populations two additional G1m alleles, Gm17,1,28 and Gm17,1,27,28) (74) (Table 7). The C region of the G1m3,1, G1m17,1 and G1m17,1,2 chains differ from that of the G1m3 chains by two, three and four amino acids, respectively (74). The correspondence between the G1m alleles and IGHG1 alleles is shown in Table 7. Thus, IGHG1*01 and IGHG1*02 are G1m17,1, IGHG1*03 is G1m3, IGHG1*04 is G1m17,1,2 and IGHG1*05 is G1m3,1. In the IGHG1 CH1, the lysine at position 120 (K120) in strand G corresponds to the G1m17 allotype (74) (Figure 2D and Figure 5B). The isoleucine I103 (strand F) is specific of the gamma1 chain isotype. If an arginine is expressed at position 120 (R120), the simultaneous presence of R120 and I103 corresponds to the expression of the G1m3 allotype (74). For the gamma3 and gamma4 isotypes (which also have R120 but T in 103), R120 only corresponds to the expression of the nG1m17 isoallotype (an isoallotype or nGm is detected by antibody reagents that identify this marker as an allotype in one IgG subclass and as an isotype for other subclasses) (74). In the IGHG1 CH3, the aspartate D12 and leucine L14 (strand A) correspond to G1m1, whereas glutamate E12 and methionine M14 correspond to the nG1m1 isoallotype (74) (Table 7). A glycine at position 110 corresponds to G1m2, whereas an alanine does not correspond to any allotype (G1m2-negative chain) (Table 7). Therapeutic antibodies are most frequently of the IgG1 isotype, and to avoid a potential immunogenicity, the constant region of the gamma1 chains are often engineered to replace the G1m3 allotype by the less immunogenic G1m17 (CH1 R120>K) (G1m17 is more extensively found in different populations) (74).

Correspondance IGHG1 G1m
References:
[11] Poiron, C. , Wu, Y., Ginestoux, C., Ehrenmann, F., Duroux, P., and Lefranc, M.-P. (2010). IMGT/mAb-DB: the IMGT® database for therapeutic monoclonal antibodies. 11èmes Journées Ouvertes de Biologie, Informatique et Mathématiques (JOBIM), Montpellier, 7-9 September 2010.
[73] Jefferis, R., and Lefranc, M.-P (2009). Human immunoglobulin allotypes: Possible implications for immunogenicity. MAbs 1(4), 332-338.
[74] Lefranc, M.-P., and Lefranc, G. (2012). Human Gm, Km and Am allotypes and their molecular characterization: a remarkable demonstration of polymorphism. In “Immunogenetics” (F. Christiansen and B. Tait, Eds.), Chap. 34. Humana Press, Springer, New York. Methods Mol Biol. 882, 635-680.

More Information:

Gm allotypes and Gm haplotypes


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