Disease relevance of IGHM

• To determine the proportion of affected patients who have defects in the micro heavy chain (IGHM) gene, we used single-stranded conformational polymorphism analysis to screen genomic DNA from 40 unrelated patients with early onset infections, profound hypogammaglobulinemia, and absent B cells [1].
• The mutation status and usage of specific VH genes such as V3-21 and V1-69 are potentially independent pathogenic and prognostic factors in chronic lymphocytic leukemia (CLL) [2].
• Protein Riv is a human gamma 1 heavy chain disease immunoglobulin variant with a deletion of the entire VH and CH1 domains and consisting of most of the hinge region plus the CH2 and CH3 domains [3].
• Previous studies have shown that a hybrid gene (designated IgT) consisting of an immunoglobulin VH gene segment and T cell receptor J alpha C alpha segments encompasses the telomeric breakpoint in SUP-T1, a cell line derived from a human T cell lymphoma [4].
• To elucidate this issue, we assayed single Reed-Sternberg cells from 12 patients with classic Hodgkin's disease of a B-cell immunophenotype to detect rearranged immunoglobulin variable-region heavy-chain (VH) genes [5].

Psychiatry related information on IGHM

• Comparisons of the amino acid sequence of the UPC-10 and A48 VH regions, and the distribution of the A48 Id family on A48, UPC-10, and three MAb, suggested that A48 regulatory idiotypes can be located on the framework segment of VH region [6].
• These effects are hypothesized to arise largely from an increase in the VH/VL association free energy that leads to tighter coupling between domain-domain association and folding [7].
• The repertoire of immunoglobulin expressed very early in human development was approached by cloning and sequencing 55 rearranged and 11 germ-line VH transcripts, after amplification by polymerase chain reaction of cDNA libraries derived from two fetal livers at 8 and 13 weeks of gestation [8].
• Human narcolepsy is tightly associated with HLA-DQB1*0602; canine narcolepsy is linked with a DNA segment with high homology with the human immunoglobulin mu-switch segment, and the onset of canine narcolepsy is associated with increased microglial expression of major histocompatibility complex DQ and DR molecules [9].
• VH and VL gene usage by anti-beta-amyloid autoantibodies in Alzheimer's disease: detection of highly mutated V regions in both heavy and light chains [10].

High impact information on IGHM

• Somatic diversification of chicken V gene segments occurs by intrachromosomal gene conversion, a DNA recombination process which involves unidirectional transfer of nucleotide sequence blocks from families of V region pseudogenes into the functional rearranged VH and VL genes [11].
• Now the three phenotypes have been shown to be due to alleles controlling the expression of three sets of VH genes all present on the same chromosome [12].
• Each antibody combining site apparently has many (estimated at 100) different specificities and most combinations of VH and VL regions probably form a viable site [12].
• Reed-Sternberg cells with B-cell phenotypes have rearranged VH genes; therefore, these cells arise from B cells [5].
• In all 12 patients, the Reed-Sternberg cells studied contained rearranged VH genes [5].

Chemical compound and disease context of IGHM

• Restricted immunoglobulin VH usage and VDJ combinations in the human response to Haemophilus influenzae type b capsular polysaccharide. Nucleotide sequences of monospecific anti-Haemophilus antibodies and polyspecific antibodies cross-reacting with self antigens [13].
• Structural basis of tyrosine sulfation and VH-gene usage in antibodies that recognize the HIV type 1 coreceptor-binding site on gp120 [14].
• We have determined the amino acid sequence of the Fv [variable heavy (VH) and variable light (VL)] region of a human monoclonal IgM-kappa with antibody activity against 3,4-pyruvylated galactose, isolated from the plasma of patient WEA with Waldenström macroglobulinemia [15].
• We studied the CD5 mRNA expression and VH gene family usage in Epstein-Barr virus (EBV)-immortalized B-cell lines derived from the blood of patients with type 1 diabetes (IDDM) of recent onset and of patients with polyneuritis cranialis multiplex (cranial neuritis; CN) [16].
• Soluble VH was expressed with an isoleucine residue at position 47 to improve expression and stability compared to VH containing a glycine residue at this position, which however was preferable for phage selection [17].

Biological context of IGHM

• Second, we present the genomic nucleotide sequence of the equine IGHD gene, which is located downstream of the IGHM gene [18].
• The AKT1 gene has been localized to human chromosome 14, band q32, proximal to the heavy-chain immunoglobulin locus (IGHM), by analysis of human-hamster somatic cell hybrids and by in situ hybridization [19].
• mRNA transcripts initiating within the human immunoglobulin mu heavy chain enhancer region contain a non-translatable exon and are extremely heterogeneous at the 5' end [20].
• To define the structure of the locus that contains the single expressed IGHM gene, two overlapping bacterial-artificial-chromosome (BAC) clones spanning the most 3' end of the channel catfish immunoglobulin heavy (IGH) chain locus have been completely sequenced [21].
• Therefore, usage of specific VH genes appears to have a strong influence on the gene expression pattern pointing to antigen recognition and ongoing BCR stimulation as a pathogenic factor in these CLL subgroups [2].

Anatomical context of IGHM

• We show that the B cell blockage at the pro-B to pre-B cell transition is due to a large homologous deletion in the IGH locus encompassing the IGHM gene leading to the inability to form a functional pre-BCR [22].
• Furthermore, the pre-BCR is stably expressed on cultured pre-BI cells from Igmu transgenic, Pax5-deficient bone marrow, but is unable to elicit its normal signaling responses [23].
• The mu-chain mRNA produced in all four cell lines was found to contain an identical deletion of most of the heavy-chain variable (VH) region (75% of the 3' portion), with no apparent alteration in constant (C) region structure [24].
• Regions of DNA from the JH to IGHM intron were cloned into reporter constructs containing the SV40 promoter and transiently transfected into chicken B and T lymphocytes [25].
• Regulation of endoplasmic reticulum stress proteins in COS cells transfected with immunoglobulin mu heavy chain cDNA [26].

Associations of IGHM with chemical compounds

• This is in contrast to the unusual Ser to Gly substitution previously found in the dolphin IGHM transmembrane region, and the functional significance of this variation for B cell antigen-receptor dimer activation remains unknown [27].
• This was observed upon expression of immunoglobulin mu chains in the absence of light chains and by treatment of cells with several agents known to cause ER stress, such as tunicamycin, brefeldin A, 2-deoxyglucose and thapsigsargin [28].
• We constructed chimeric receptor chains in which an immunoglobulin heavy chain variable region (VH) from a phosphorylcholine-specific antibody is substituted for T cell receptor (Tcr) alpha and beta V regions [29].
• Junctional adhesion molecules are a family of glycoproteins characterised by two immunoglobulin folds (VH- and C2-type) in the extracellular domain [30].
• The mouse antibody response to infection with Cryptococcus neoformans: VH and VL usage in polysaccharide binding antibodies [31].

Physical interactions of IGHM

• The immunoglobulin mu heavy-chain gene enhancer contains closely juxtaposed binding sites for ETS and leucine zipper-containing basic helix-loop-helix (bHLH-zip) proteins [32].
• The B-lymphocyte-specific activity of the immunoglobulin mu heavy-chain gene enhancer has been attributed to the octamer motif (ATTTGCAT) present within the enhancer that binds a B-cell-specific factor designated NF-A2/OTF-2 [33].

Other interactions of IGHM

• The human heavy chain disease protein BW is an immunoglobulin mu-chain variant whose amino terminus is initiated at the fifth amino acid of the first constant region domain [34].
• A pre-BCR contains two immunoglobulin mu-heavy chains (muHC), two surrogate light chains (SLC) consisting of the non-covalently associated polypeptides, VpreB and lambda5, and the heterodimeric signaling transducer Igalpha/beta [35].
• Thus, the association of psi L chains with mu does not bring about a bias in the VH gene usage, but a first selection on the CDR3 region could be the result of recognition by given autoantigens or ligands different for preB cells and B cells [36].
• The abnormal YAO alpha 1 Ig was devoid of VH and CH1 domains and started at the beginning of the hinge region [37].
• SUMO modification of a novel MAR-binding protein, SATB2, modulates immunoglobulin mu gene expression [38].

Analytical, diagnostic and therapeutic context of IGHM

• Genomic Southern blot analyses showed that the dolphin IGHM gene is most likely present in a single copy, and its sequence shows greatest similarity to those of the IGHM gene of the sheep, pig and cow, evolutionarily related artiodactyls [39].
• All VH families were identified and further analysis focused on VH3 sequence analysis of 37 distinct VDJ cDNA clones [40].
• Comparative gene mapping in mammals suggests that the bovine immunoglobulin heavy chain genes, IGHG4 and IGHM might be syntenic with the FOS oncogene [41].
• That these contacts are involved with DNA binding is supported by recurrent features of a newly compiled set of homology groups of 13 variable regions of heavy chains (VH) and 11 variable regions of light chains (VL), characteristic pattern of somatic mutations, and the results of site-directed mutagenesis [42].
• The observed differences between cDNA sequences selected and the sequences of segmental elements derived from conventional genomic libraries as well as from VH segment-specific libraries generated by direct PCR amplification of genomic DNA indicate that the VH repertoire is diversified by both junctional diversity and somatic mutation [43].

References