IGH

Summary

IGH (immunoglobulin heavy locus, HGNC:5477) is a protein-coding gene on chromosome 14q32.33.

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. During B cell development, a recombination event at the DNA level joins a single D segment with a J segment; this partially rearranged D-J gene is then joined to a V segment. The rearranged V-D-J is then transcribed with 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 V-D-J gene is brought in proximity to one of the IGHG, IGHA, or IGHE genes and each cell expresses either the gamma, alpha, or epsilon heavy chain. 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 deoxynucleotidyltransferase, and by somatic hypermutation, which occurs during B cell maturation in the spleen and lymph nodes. Due to polymorphism, the numbers of functional V, J, and D genes differ among individuals and some V, D, J, and C segments may be pseudogenes.

Source: NCBI Gene 3492 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 105 total — 6 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 32

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5477
Approved symbol	IGH
Name	immunoglobulin heavy locus
Location	14q32.33
Locus type	gene with protein product
Status	Approved
OMIM	146910, 147010, 147070
Entrez	3492

Gene structure

Transcript identifiers

Ensembl transcripts: 0

RefSeq mRNA: 0 — MANE Select: None

Canonical transcript exons

None — 0 exons

Expression profiles

Top tissues by expression

0 total, by Bgee expression score (0-100, higher = more expressed):

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, DLX4, ELF1, KMT2A, PAX5, POU2F1, POU2F2, SPI1, SPIC, TCF3

Literature-anchored findings (GeneRIF, showing 40)

• Internal IgH class switch region deletions are position-independent and enhanced by AID expression (PMID:12114543)
• localized an origin of replication in MEL cells to a 3-kb segment located between the 3’ Igh regulatory region and Crip (PMID:12370427)
• Imprint of somatic hypermutation differs in immunoglobulin heavy and lambda chain variable gene segments. (PMID:12749909)
• Physical location at the V(H) locus is involved in in different stages of B cell development in b-cell acute lymphoblastic leukemia in children. (PMID:15010366)
• Rearrangements of the BCL6 locus were detected in five B-cell lymphomas of the leg, and involved IGH (two cases), IGL (one case), and non-IG genes (two cases). (PMID:15191563)
• This study identifies FOXP1 as a new translocation partner of IGH in a site-dependent subset of MALT lymphomas. (PMID:15703784)
• frequency and chromosomal features of this der(8)t(8;14;18) in a series of acute leukaemias and malignant lymphomas (PMID:15716988)
• analysis of the VH gene is important for predicting the clinical course of CD5+ diffuse large B-cell lymphoma (PMID:15717690)
• We present here a case of Follicular Lymphoma with leukemic presentation and a complex translocation involving the IgH, BCL2 and BCL6 loci (PMID:16194898)
• The low frequency of BCL-2/IgH translocation in healthy Chinese individuals of Han nationality located in Zhejiang area may be one of the reasons for the difference in the incidence of follicular lymphoma between China and Western countries. (PMID:16215945)
• The results show that all hybridoma cells analyzed rearranged exclusively the IGHV1-2 gene, in contrast with naive spleen B cells that used three out of the five IGHV genes present in the transgene. (PMID:16343622)
• IGHJ and IGHD gene mutations are associated with chronic lymphocytic leukemia (PMID:17169423)
• study suggests that chronic lymphocytic leukaemia with increased prolymphocytes (CLL/PL) is a relatively homogeneous disease regarding VH gene mutation, but heterogeneous regarding genetic lesions (PMID:17410523)
• Objective criteria are described for identification of immunoglobulin heavy chain diversity (IGHD) genes, with all possible mutation levels, in junctions of different lengths. (PMID:17553518)
• IGHV gene mutation is associated with chronic lymphocytic leukemia (PMID:17914413)
• translocation, t(6;14)(p22;q32), involving IGH@ as a novel recurrent translocation in 13 b-cell precursor acute lymphoblastic leukemia patients (PMID:17940204)
• among gastrointestinal MALT lymphomas, t(14;18)-(IgH;Bcl-2) translocation clusters in hepatitis C-positive patients sustaining the role of HCV infection in the lymphoma development (PMID:18538438)
• Novel IGH translocations, t(2;14)(q14.3;q2) and t(14;17)(q32;q21), in B-cell precursor acute lymphoblastic leukemia are reported. (PMID:18656697)
• IGHG genotype is important in defense against meningococci in individuals with low complement function and possibly in combination with other immunodeficiencies. (PMID:18667363)
• 2 BCP-ALL patients had a novel, recurrent, reciprocal translocation involving IGH@ & EPOR. EPOR mRNA expression was increased at diagnosis and relapse. (PMID:18818706)
• JAK2V617F-positive essential thrombocythemia and multiple myeloma with IGH/CCND1 gene translocation coexist, but originate from separate clones (PMID:19129688)
• IGHV rearrangement analysis in splenic marginal zone B-cell lymphoma reveals a non-random preference for use of IGHV1-2, IGHV3-23 and IGHV3-30 genes, whose presence differs according to clinical features and prognostic category. (PMID:19250848)
• Deletion of 5’IGH, corresponding to the variable IGH segment (IGH(V)) was the most recurrent aberration, observed in 82% (the second most common finding among our patients). (PMID:19264231)
• Results support the use of LPL and ADAM29 gene expression associated to IGHV mutational status for predicting the clinical outcome of patients treated by oral fludarabine + cyclophosphamide and could be considered for treatment strategies. (PMID:19340428)
• Chronic lymphocytic leukemia With t(2;14)(p16;q32) involves the BCL11A and IgH genes and is associated with atypical morphologic features and unmutated IgVH genes. (PMID:19369625)
• significant fraction of splenic marginal zone lymphomas derive from naive B-cells with unmutated IgVH genes indicating heterogeneous group of diseases with respect to cell origin; prognostic significance of mutation status was not observed in this study (PMID:19443409)
• CCNE1 is a novel IGH translocation partner in t(14;19)(q32;q12) in diffuse large B-cell lymphoma (PMID:19454496)
• Studies indicate that among the multitude of prognostic markers evaluated in CLL patients, IgVH mutational status, ZAP-70, and CD38 are some of the most frequently reported. (PMID:19679010)
• Human plasma cells were isolated from tonsil, blood, and bone marrow, their IGHV3 and IGHV6 genes were sequenced, and their somatic hypermutation were evaluated (PMID:19915167)
• The molecular characterization of the IGH-MALT1 fusion products in 5 new cases of t(14;18)-positive mucosa-associated lymphoid tissue lymphomas, is reported. (PMID:19965626)
• we identified CD44, located on chromosome 11p13, as a novel translocation partner of IGH in 9 of 114 cases of gastric, nongastric extranodal, follicular, and nodal diffuse large B-cell lymphoma (PMID:20093404)
• BCL2, BCL6 expression, and BCL2/IGH translocation had no impact on overall survival in adult, diffuse large B-cell lymphoma patients (PMID:20160358)
• IgVh mutational status, ZAP-70 protein and 6q- are powerful prognostic markers for patients with chronic lymphocytic leukemia (PMID:20164537)
• Q-PCR results demonstrated VH2 genes were overexpressed in ankylosing spondylitis patients (Relative amount of mRNA of VH2 genes to a house-keeping gene, 7.13+/-7.77 vs, 0.68+/-0.55; P<0.0001). (PMID:20177145)
• This protein has been found differentially expressed in thalami from patients with schizophrenia. (PMID:20471030)
• BLID upregulation resulting from a novel IGH translocation is associated with childhood B-Cell precursor acute lymphoblastic leukemia. (PMID:20544842)
• this is the first report that describes variant rearrangements of IGH/BCL2 genes associated to atypical FISH patterns in follicular lymphoma (PMID:20952062)
• Methylation markers identify high risk patients in IGHV mutated chronic lymphocytic leukemia (PMID:21051931)
• Data indicate that high iLR expression was strongly correlated with negativity for CD38 and ZAP-70 expression and mutated IGVH gene status. (PMID:21055809)
• Data show that IgG heavy chains and IgG receptors were detected in the intraocular epithelium and endothelium. (PMID:21061041)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Canonical reviewed UniProt: None (reviewed: )

All UniProt accessions (0):

RefSeq proteins (0): (*=MANE)

Domains & families (InterPro)

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 0 (showing top):

GO Biological Process (0):

GO Molecular Function (0):

GO Cellular Component (0):

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

0 interactions, top by confidence:

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

105 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	2
Uncertain significance	0
Likely benign	13
Benign	78

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
14808	NC_000014.9:g.105643212dup	Pathogenic
14810	NC_000014.9:g.105854405C>T	Pathogenic
14812	NC_000014.9:g.105855623_105855624del	Pathogenic
14813	NC_000014.9:g.105855107C>T	Pathogenic
156278	NC_000014.9:g.105854468A>C	Pathogenic
427234	NC_000014.9:g.105856087G>A	Pathogenic
1339539	NC_000014.9:g.105856013G>T	Likely pathogenic
973583	NC_000014.9:g.105855132dup	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

Disease associations

OMIM: gene MIM:146910, MIM:147010, MIM:147070 | disease phenotypes: MIM:601495

GenCC curated gene-disease

Mondo (2): autosomal recessive agammaglobulinemia 1 (MONDO:0020729), primary ovarian failure (MONDO:0005387)

Orphanet (1): NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000505	Visual impairment
HP:0000614	Abnormal nasolacrimal system morphology
HP:0000820	Abnormality of the thyroid gland
HP:0000975	Hyperhidrosis
HP:0001004	Lymphedema
HP:0001287	Meningitis
HP:0001541	Ascites
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001903	Anemia
HP:0001945	Fever
HP:0002017	Nausea and vomiting
HP:0002019	Constipation
HP:0002027	Abdominal pain
HP:0002039	Anorexia
HP:0002113	Pulmonary infiltrates
HP:0002202	Pleural effusion
HP:0002205	Recurrent respiratory infections
HP:0002585	Abnormal peritoneum morphology
HP:0002665	Lymphoma
HP:0002716	Lymphadenopathy
HP:0003072	Hypercalcemia
HP:0005561	Abnormal bone marrow cell morphology
HP:0011024	Abnormality of the gastrointestinal tract
HP:0012123	Posterior uveitis
HP:0012191	B-cell lymphoma
HP:0012378	Fatigue
HP:0025435	Increased circulating lactate dehydrogenase concentration
HP:0030166	Night sweats
HP:0033823	Mediastinal mass

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002245_29	Alzheimer’s disease (late onset)	3.000000e-07
GCST004924_6	IgG monogalactosylation phenotypes (multivariate analysis)	4.000000e-17
GCST004925_8	IgG N-glycosylation phenotypes (multivariate analysis)	6.000000e-17
GCST004927_9	IgG galactosylation phenotypes (multivariate analysis)	3.000000e-18
GCST004928_5	IgG bisecting N-acetyl glucosamine phenotypes (multivariate analysis)	1.000000e-12
GCST004929_5	IgG fucosylation phenotypes (multivariate analysis)	4.000000e-19
GCST004930_7	IgG sialylation phenotypes (multivariate analysis)	2.000000e-12
GCST004932_2	IgG monosialylation phenotypes (multivariate analysis)	1.000000e-12
GCST005925_2	Baseline cortisol levels in response to low dose short synacthen test in corticosteroid treated asthma	3.000000e-07

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0008423	IgG monogalactosylation measurement
EFO:0005193	serum IgG glycosylation measurement
EFO:0008425	IgG galactosylation measurement
EFO:0008426	IgG bisecting N-acetyl glucosamine measurement
EFO:0008427	IgG fucosylation measurement
EFO:0008428	IgG sialylation measurement
EFO:0008430	IgG monosialylation measurement
EFO:0005843	cortisol measurement
EFO:0009175	response to synacthen

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CGP 52608	affects binding, increases reaction	1
(+)-JQ1 compound	affects binding, decreases reaction	1
Dasatinib	decreases response to substance	1
Arsenic	increases methylation	1
Cadmium	affects binding	1
Copper	affects binding	1
Etoposide	increases mutagenesis	1
Lead	affects binding	1
Nickel	affects binding	1
Valproic Acid	increases methylation	1
Zinc	affects binding	1
Aflatoxin B1	decreases methylation	1
Permethrin	increases mutagenesis, increases expression	1

Cellosaurus cell lines

590 cell lines: 588 cancer cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0008	Daudi	Cancer cell line	Male
CVCL_0012	LP-1	Cancer cell line	Female
CVCL_0092	NALM-6	Cancer cell line	Male
CVCL_0511	Raji	Cancer cell line	Male
CVCL_0539	SU-DHL-4	Cancer cell line	Male
CVCL_0597	Ramos	Cancer cell line	Male
CVCL_0R19	B-THP-1	Cancer cell line	Male
CVCL_0R20	B-THP-1/DC-SIGN	Cancer cell line	Male
CVCL_0R22	Raji/DC-SIGN	Cancer cell line	Male
CVCL_0U51	NALM-6/SP-B	Cancer cell line	Male

Clinical trials (associated diseases)

75 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists