IGH@

IGH
Identifiers
Aliases	IGH, IGD1, IGH.1@, IGH@, IGHD@, IGHDY1, IGHJ, IGHJ@, IGHV, IGHV@, immunoglobulin heavy locus, IgH locus
External IDs	OMIM: 146910, 147010, 147070; MGI: 96442; GeneCards: IGH
Orthologs Databases NCBI: entry Species Human Mouse Entrez 3492 111507 Ensembl n/a n/a UniProt n a n/a RefSeq (mRNA) n/a n/a RefSeq (protein) n/a n/a Location (UCSC) n/a n/a PubMed search
Wikidata
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Immunoglobulin heavy locus, also known as IGH@, is a region on human chromosome 14 that contains many gene segments for the heavy chains of human antibodies (or immunoglobulins). The @ notation indicates its designation as a gene cluster: IGH@ is a collection of many gene segments.

Immunoglobulins recognize foreign antigens and initiate immune responses such as phagocytosis and the complement system. Each immunoglobulin molecule consists of two identical heavy chains and two identical light chains. This region represents the germline organization of the heavy chain locus. The locus includes V (variable), D (diversity), J (joining), and C (constant) segments.

Structure

The heavy chain locus (IGH@) is arranged in a manner of V_n-D_x-J_y-C_z, with a number of possible Variable, Diversity, Joining, and Constant segments to "choose" from. Due to the extensive assembly needed, none of the named parts of the IGH@ locus are "protein-coding genes" in the traditional sense.

The V, D, and J segments are arranged in a manner suited for V(D)J recombination, with conserved recombination signal sequences (RSS) between them to lead to the intended joining of one each of V, D, and J into one exon. In other words, they are only partial exons surrounded by RSS.

The C segments each consists of multiple exons arranged in a manner suitable for class switch recombination, making them more "gene-like". Each C segment consists of:

• A conserved conserved nucleotide motif called a switch (S) region, found in all H chains (i.e. S_μ, S_γ3, etc.) except the IgD chain.
• A number of C (constant) exons, which encode an immunoglobulin-fold constant domain, except in a few mammalian C2 codons where it encodes a flexible "hinge" derived from the bulky domain.
• A poly-A tract.
• One or more m (membrane) exons, which encode the transmembrane region found on the B cell receptor (BCR) versions of the antibody.
• Another poly-A tract, after which another segment begins.

The stop codon for the final mRNA lies in the last exon of the C segment. Whether it occurs before the transmembrane regions is a matter of alternative splicing. This determines whether an anchored BCR or a free-floating antibody is made.

Pseudogenes

A V/D/J segment may be considered a pseudogene if it contains a mutation in the RSS (making it unable to be spliced in) or a mutation that prevents it from producing a functional antibody. In the latter case, it differs from a traditional pseudogene in that the protein product is expressed and made, but the resultant B cell lineage quickly dies out in the selection process.

There are also V/D/J "orphon" pseudogenes outside of the IGH@ locus, in which case their location prevents their incorporation into mRNAs by the recombination system.

There are at least two C pseudogenes in most humans: IGHGP, IGHEP1.

Function

During B cell development, V(D)J recombination at the DNA level joins a single D segment with a J segment; the fused D-J exon of this partially rearranged D-J region is then joined to a V segment. The rearranged V-D-J region containing a fused V-D-J exon is then transcribed and fused at the RNA level to the IGHM constant region; this transcript encodes a mu heavy chain. Later in development B cells generate V-D-J-Cmu-Cdelta pre-messenger RNA, which is alternatively spliced to encode either a mu or a delta heavy chain.

Mature B cells in the lymph nodes undergo switch recombination, so that the fused V-D-J gene segment is brought in proximity to one of the IGHG, IGHA, or IGHE gene segments and each cell expresses either the gamma, alpha, or epsilon heavy chain. Potential recombination of many different V segments with several J segments provides a wide range of antigen recognition. Additional diversity is attained by junctional diversity, resulting from the random addition of nucleotides by terminal deoxynucleotidyl transferase, and by somatic hypermutation, which occurs during B cell maturation in the spleen and lymph nodes. Several V, D, J, and C segments are known to be incapable of encoding a protein and are considered pseudogenous gene segments (often simply referred to as pseudogenes).

Nomenclature

V, D, J segments

Symbols for variable (V) immunoglobulin gene segments start with IGHV and include two or three numbers separated by dashes. Examples:

IGHV1-2, IGHV1-3, …, IGHV1-69-2, IGHV2-5, …, IGHV7-4-1

Symbols for diversity (D) immunoglobulin gene segments start with IGHD and include two numbers separated by dashes. Examples:

IGHD1-1, IGHD1-7, …, IGHD7-27

Symbols for joining (J) immunoglobulin gene segments:

IGHJ1, IGHJ2, IGHJ3, IGHJ4, IGHJ5, IGHJ6

The clusters formed by those segments may be called IGHV@, IGHD@, and IGHJ@. The @ is mandatory, especially in the case of the D segments, because otherwise it would be confused with the delta constant region.

Constant segments

Constant segments each consists of multiple exons and are often annotated as "genes". In a 5' to 3' order, the human ones are:

1. IGHM μ - IgM
2. IGHD δ IgD
3. IGHG3 γ₃ - IgG3
4. IGHG1 γ₁ - IgG1
5. IGHA1 α₁ - IgA1
6. IGHG2 γ₂ - IgG2
7. IGHG4 γ₄ - IgG4
8. IGHE ε - IgE
9. IGHA2 α₂ - IgA2

Clinical significance

In B-cell neoplasms such as chronic lymphocytic leukemia, mutations of IGHV are associated with better response to treatment and longer survival.

(See also the pages for constant-region genes for more information.)

See also

• IGHV@

Further reading

• Tomlinson IM, Cook GP, Walter G, Carter NP, Riethman H, Buluwela L, et al. (September 1995). "A complete map of the human immunoglobulin VH locus". Annals of the New York Academy of Sciences. 764 (1): 43–46. Bibcode:1995NYASA.764...43T. doi:10.1111/j.1749-6632.1995.tb55804.x. PMID 7486559. S2CID 43106266.
• Word CJ, White MB, Kuziel WA, Shen AL, Blattner FR, Tucker PW (1989). "The human immunoglobulin C mu-C delta locus: complete nucleotide sequence and structural analysis". International Immunology. 1 (3): 296–309. doi:10.1093/intimm/1.3.296. PMID 2518659.
• Buluwela L, Rabbitts TH (1989). "A VH gene is located within 95 Kb of the human immunoglobulin heavy chain constant region genes". European Journal of Immunology. 18 (11): 1843–1845. doi:10.1002/eji.1830181130. PMID 3144456. S2CID 21128167.
• Ichihara Y, Matsuoka H, Kurosawa Y (1989). "Organization of human immunoglobulin heavy chain diversity gene loci". The EMBO Journal. 7 (13): 4141–4150. doi:10.1002/j.1460-2075.1988.tb03309.x. PMC 455124. PMID 3243276.
• Ravetch JV, Siebenlist U, Korsmeyer S, Waldmann T, Leder P (December 1981). "Structure of the human immunoglobulin mu locus: characterization of embryonic and rearranged J and D genes". Cell. 27 (3 Pt 2): 583–591. doi:10.1016/0092-8674(81)90400-1. PMID 6101209. S2CID 20229287.
• Flanagan JG, Rabbitts TH (1983). "Arrangement of human immunoglobulin heavy chain constant region genes implies evolutionary duplication of a segment containing gamma, epsilon and alpha genes". Nature. 300 (5894): 709–713. doi:10.1038/300709a0. PMID 6817141. S2CID 4335031.
• Mills FC, Harindranath N, Mitchell M, Max EE (1997). "Enhancer complexes located downstream of both human immunoglobulin Calpha genes". The Journal of Experimental Medicine. 186 (6): 845–858. doi:10.1084/jem.186.6.845. PMC 2199054. PMID 9294139.
• Matsuda F, Ishii K, Bourvagnet P, Kuma KI, Hayashida H, Miyata T, et al. (December 1998). "The complete nucleotide sequence of the human immunoglobulin heavy chain variable region locus". The Journal of Experimental Medicine. 188 (11): 2151–2162. doi:10.1084/jem.188.11.2151. PMC 2212390. PMID 9841928.
• Dudley DD, Manis JP, Zarrin AA, Kaylor L, Tian M, Alt FW (July 2002). "Internal IgH class switch region deletions are position-independent and enhanced by AID expression". Proceedings of the National Academy of Sciences of the United States of America. 99 (15): 9984–9989. Bibcode:2002PNAS...99.9984D. doi:10.1073/pnas.152333499. PMC 126611. PMID 12114543.
• Zhou J, Ashouian N, Delepine M, Matsuda F, Chevillard C, Riblet R, et al. (October 2002). "The origin of a developmentally regulated Igh replicon is located near the border of regulatory domains for Igh replication and expression". Proceedings of the National Academy of Sciences of the United States of America. 99 (21): 13693–13698. Bibcode:2002PNAS...9913693Z. doi:10.1073/pnas.212392399. PMC 129745. PMID 12370427.
• Li A, Rue M, Zhou J, Wang H, Goldwasser MA, Neuberg D, et al. (June 2004). "Utilization of Ig heavy chain variable, diversity, and joining gene segments in children with B-lineage acute lymphoblastic leukemia: implications for the mechanisms of VDJ recombination and for pathogenesis". Blood. 103 (12): 4602–4609. doi:10.1182/blood-2003-11-3857. PMID 15010366.
• Hallermann C, Kaune KM, Gesk S, Martin-Subero JI, Gunawan B, Griesinger F, et al. (July 2004). "Molecular cytogenetic analysis of chromosomal breakpoints in the IGH, MYC, BCL6, and MALT1 gene loci in primary cutaneous B-cell lymphomas". The Journal of Investigative Dermatology. 123 (1): 213–219. doi:10.1111/j.0022-202X.2004.22720.x. PMID 15191563.
• Sepulveda MA, Garrett FE, Price-Whelan A, Birshtein BK (2005). "Comparative analysis of human and mouse 3' Igh regulatory regions identifies distinctive structural features". Molecular Immunology. 42 (5): 605–615. doi:10.1016/j.molimm.2004.09.006. PMID 15607820.
• Streubel B, Vinatzer U, Lamprecht A, Raderer M, Chott A (April 2005). "T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma". Leukemia. 19 (4): 652–658. doi:10.1038/sj.leu.2403644. PMID 15703784.
• Knezevich S, Ludkovski O, Salski C, Lestou V, Chhanabhai M, Lam W, et al. (April 2005). "Concurrent translocation of BCL2 and MYC with a single immunoglobulin locus in high-grade B-cell lymphomas". Leukemia. 19 (4): 659–663. doi:10.1038/sj.leu.2403661. hdl:2381/15869. PMID 15716988.
• Rack K, Delannoy A, Ravoet C, Vannuffel P, Hamels J, Gillerot Y (October 2005). "Translocation of BCL2 and BCL6 to the same immunoglobulin heavy chain locus in a case of follicular lymphoma". Leukemia & Lymphoma. 46 (10): 1513–1516. doi:10.1080/10428190500125648. PMID 16194898. S2CID 10501344.

• Matsuda F, Shin EK, Hirabayashi Y, et al. (1990). "Organization of variable region segments of the human immunoglobulin heavy chain: duplication of the D5 cluster within the locus and interchromosomal translocation of variable region segments". EMBO J. 9 (8): 2501–6. doi:10.1002/j.1460-2075.1990.tb07429.x. PMC 552279. PMID 2114977.
• Cherif D, Berger R (1991). "New localizations of VH sequences by in situ hybridization with biotinylated probes". Genes Chromosomes Cancer. 2 (2): 103–8. doi:10.1002/gcc.2870020205. PMID 2126193. S2CID 22489747.
• Toyonaga B, Yoshikai Y, Vadasz V, et al. (1986). "Organization and sequences of the diversity, joining, and constant region genes of the human T-cell receptor beta chain". Proc. Natl. Acad. Sci. U.S.A. 82 (24): 8624–8. doi:10.1073/pnas.82.24.8624. PMC 390970. PMID 3866244.
• Matthyssens G, Rabbitts TH (1981). "Structure and multiplicity of genes for the human immunoglobulin heavy chain variable region". Proc. Natl. Acad. Sci. U.S.A. 77 (11): 6561–5. doi:10.1073/pnas.77.11.6561. PMC 350325. PMID 6450418.
• Mariette X, Tsapis A, Brouet JC (1993). "Nucleotidic sequence analysis of the variable domains of four human monoclonal IgM with an antibody activity to myelin-associated glycoprotein". Eur. J. Immunol. 23 (4): 846–51. doi:10.1002/eji.1830230412. PMID 7681398. S2CID 38756102.
• Boursier L, Su W, Spencer J (2003). "Imprint of somatic hypermutation differs in human immunoglobulin heavy and lambda chain variable gene segments". Mol. Immunol. 39 (16): 1025–34. doi:10.1016/S0161-5890(03)00033-6. PMID 12749909.
• Nakamura N, Nakamura S, Yamaguchi M, et al. (2005). "CD5+ diffuse large B-cell lymphoma consists of germline cases and hypermutated cases in the immunoglobulin heavy chain gene variable region". Int. J. Hematol. 81 (1): 58–61. doi:10.1532/IJH97.04119. PMID 15717690. S2CID 22639228.
• Suárez E, Magadán S, Sanjuán I, et al. (2006). "Rearrangement of only one human IGHV gene is sufficient to generate a wide repertoire of antigen specific antibody responses in transgenic mice". Mol. Immunol. 43 (11): 1827–35. doi:10.1016/j.molimm.2005.10.015. PMID 16343622.
• Balogh Z, Reiniger L, Deák L, et al. (2007). "IgVH gene mutation status and genomic imbalances in chronic lymphocytic leukaemia with increased prolymphocytes (CLL/PL)". Hematological Oncology. 25 (2): 90–5. doi:10.1002/hon.812. PMID 17410523. S2CID 19587621.