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PubMed2007

Study of variant anatomical structures (bony canals, fibrous bands, and muscles) in relation to potential supraclavicular nerve entrapment.

Since the definition of supraclavicular nerve entrapment syndrome by Gelberman et al. (Gelberman et al. [1975] J. Bone Joint Surg. Am. 57:119) a number of clinical cases of this specific entrapment neuropathy have been reported. In all these cases, the nerve injury has been attributed to the location of the supraclavicular nerve branch in a narrow canal in the clavicle. However, in the anatomical literature, variations in the course of the supraclavicular nerves have not only been ascribed to bony canals but also to abnormal fibrous and muscular structures. Considering the fact that the existence of a narrow site with rigid walls along the course of a nerve is essential for the development of an entrapment neuropathy, our study examines all the variant anatomical structures with a possible role in supraclavicular nerve entrapment. We describe three groups of anatomical structures with close relation to the course of the supraclavicular nerves-transclavicular canals, fibrous bands, and unusual muscular structures. Based on the characteristics of the variations found, for the first time, we suggest that in addition to the bony canals through the clavicle certain fibrous and muscular structures could also be an anatomical basis for supraclavicular nerve entrapment syndrome.

Aged↗

PubMed2026

Long-read sequencing resolves complex CYP21A2 variants and identifies 2+0 carriers in 21-hydroxylase deficiency.

The complex CYP21A2 variants arising from high homology with its pseudogene CYP21A1P challenge the diagnosis of 21-hydroxylase deficiency (21-OHD). This study systematically evaluated long-read sequencing (LRS) for identifying complex structural variants of the CYP21A2 gene in 21-OHD in comparison with conventional molecular diagnostic methods, including multiplex ligation-dependent probe amplification (MLPA), CNVplex, and SNaPshot. Twenty patients with suspected 21-OHD and defined CYP21A2 structural variants identified via initial MLPA screening were enrolled. Variants were further analyzed using CNVplex and SNaPshot, then all samples underwent LRS for comprehensive variant detection, breakpoint mapping, and haplotype resolution. LRS overcame key limitations of conventional methods. It reliably identified a novel large-fragment deletion and defined its boundaries. Notably, LRS identified "2+0" carriers, where deletions masked by duplications cause false-negatives with standard techniques. Moreover, LRS accurately distinguished CYP21A1P/CYP21A2_CH-4 and CH-9 chimera subtypes which were indistinguishable by the combined conventional assays. Furthermore, LRS enabled the precise identification and characterization of TNXA/TNXB chimeric deletions. These are frequently misclassified as CYP21A1P/CYP21A2 chimeras by conventional methods but are critical for diagnosing associated conditions such as CAH-X syndrome. LRS provides a superior, integrated solution for the molecular diagnosis of 21-OHD, offering precise structural variant characterization, accurate carrier detection, and reliable breakpoint mapping. Its application enhances diagnostic accuracy, supports advanced genetic counseling, and paves the way for genotype-informed clinical management.

Journal Article↗

PubMed1993

Inside-out integrin signaling in macrophages. Analysis of the role of the alpha 6A beta 1 and alpha 6B beta 1 integrin variants in laminin adhesion by cDNA expression in an alpha 6 integrin-deficient macrophage cell line.

Leukocytes use the alpha 6 beta 1 integrin to adhere to laminin based on mAb inhibition and affinity chromatography studies. This adhesion requires leukocyte stimulation with either PMA or specific cytokines, a process that has been termed "inside-out" integrin signaling. In the present study, the involvement of alpha 6 integrin structural variants in this regulated adhesion was examined using mouse macrophages. The two known alpha 6 structural variants, alpha 6A and alpha 6B, differ only in their cytoplasmic domain sequences. Using reverse transcriptase-polymerase chain reaction, we observed that macrophages express only the alpha 6A structural variant, in contrast to most cell types which express both alpha 6A and alpha 6B variants. The role of this integrin subunit in macrophage adhesion was assessed by cDNA transfection of P388D1 cells. We found that this mouse macrophage cell line does not adhere to laminin even in response to phorbol 12-myristate 13-acetate (PMA) stimulation, though it does adhere normally to fibronectin and tissue culture plastic. Subsequent analysis employing reverse transcriptase-polymerase chain reaction and immunoprecipitation of surface labeled cells revealed that this cell line expresses neither the alpha 6A nor alpha 6B integrin subunits. Stable transfection of either the chick or human alpha 6A cDNAs into P388D1 cells resulted in chimeric alpha 6A beta 1 surface expression. The alpha 6A transfectants exhibited inside-out integrin signaling because PMA stimulation markedly increased their ability to adhere to laminin but it did not increase alpha 6A beta 1 surface expression. Similar results were obtained after transfection of the human alpha 6B cDNA. Analysis of the human transfectants was facilitated by the generation of a monoclonal antibody, 2B7, that is specific for the human alpha 6 integrin subunit. These observations demonstrate that both alpha 6A beta 1 and alpha 6B beta 1 can be regulated by inside-out signaling pathways in macrophages, even though this cell type expresses only alpha 6A beta 1. The data presented also demonstrate clearly that the alpha 6A and alpha 6B cytoplasmic domains do not differ in their ability to be regulated by PMA.

Amino Acid Sequence↗

PubMed2006

Histone variants--the structure behind the function.

In recent years, the chromatin field has witnessed a renewed interest in histone variants as pertaining to their structural role, but mainly because of the functional specificity they impart to chromatin. In this review, I am going to discuss several of the most recent structural studies on core histone (H2A.Bbd, H2A.Z, H2A.X, macroH2A, H3.3, CENP-A) and linker histone variants (histone H1 microheterogeneity) focusing on their role in nucleosome stability and chromatin fibre dynamics with special emphasis on their possible functional implications. The data accumulated to date indicates that histone variability plays an important role in the histone-mediated regulation of chromatin metabolism. Understanding and deciphering the underlying structural amino acid code behind such variability remains one of the most exciting future challenges in chromatin research.

Amino Acid Sequence↗

PubMed1979

Carbohydrate of the human plasminogen variants. III. Structure of the O-glycosidically linked oligosaccharide unit.

The preceding two manuscripts in this issue (Hayes, M. L., and Castellino, F. J. (1979) J. Biol. Chem. 254, 8768-8771, 8772-8776) describe the isolation and characterization of glycopeptides from human plasminogen affinity chromatography variants 1 and 2. Plasminogen variant 1 contains an asparagine288-based branched carbohydrate structure, which has been established in the immediately preceding manuscript. This structure is absent in variant 2. Plasminogen variants 1 and 2 contain a threonine-based glycoconjugate. This latter structure has been established by combination of methylation data, glycosidase digestions, periodate oxidations, and Smith degradations of the beta-eliminated reduced oligosaccharides. One glycopeptide unit, isolated from both plasminogen variants 1 (1D) and 2 (2D) possessed the following structure: Sia alpha 2 yields 3Gal beta 1 yields 3GalNAc-Thr. The threonine was found to be residue 345 in the Glu-plasminogen sequence. Another glycopeptide unit was also found to be present, in lower yields in both variants 1 (1E) and 2 (2E). The structure of this unit was: Sia alpha 2 yields 3Gal beta1 yields 3GalNAc-Thr. : formula: (see text), alpha 2,6 Sia. Again Thr 345 was the glycosylated amino acid. The amino acid sequence around the glycosylated threonine was found to be NH2-Ala.Pro.Thr(CHO).Ala.Pro.Pro.Glu.

Amino Acid Sequence↗

PubMed1995

A multiple site-specific DNA-inversion model for the control of Omp1 phase and antigenic variation in Dichelobacter nodosus.

The molecular cloning and sequence analysis of four structurally variant linked genes (omp1A,B,C,D) that encode the major outer membrane protein of Dichelobacter nodosus strain VCS1001 are described. The isolation of rearranged copies of omp1A and omp1B, and the identification in the 5' regions of all four genes of short cross-over-site sequences that were similar to the Din family of cross-over-site sequences, suggested that site-specific DNA inversion was involved in omp1 rearrangement. Evidence for site-specific inversion of the 497 bp DNA fragment, which was located between the divergently orientated omp1A and omp1B genes, and which contained the promoter and 5' coding sequence of Omp1, was obtained by polymerase chain reaction-mediated amplification of inverted forms of these genes. However, to account for all of the omp1 gene copies cloned in this study, a more widespread inversion phenomenon must be involved in the rearrangement of these genes and a model for multiple site-specific DNA inversions at the omp1 locus is described. In this model the four structurally variant omp1 genes can be assembled from one of four structurally variant C-terminal coding regions and a conserved N-terminal coding region and can be expressed from a single promoter. It is postulated that this genetic capability endows D. nodosus with the ability to switch the antigenic specificity of one of its major surface proteins.

Amino Acid Sequence↗

PubMed2025

Whole-genome sequencing, as a powerful diagnostic tool in hearing loss, reveals novel variants in PTPRQ missed by whole-exome sequencing.

BACKGROUND/OBJECTIVES: Hearing loss (HL) is one of the most common congenital disorders, affecting 1-2 in 1,000 newborns. Modern genetic diagnostics using large gene panels and/or whole exome analysis (WES) can identify disease-causing mutations in 25-50 % of patients, with higher solve rates in individuals with earlier onset. RESULTS: Here, we used whole-genome sequencing (WGS) to reanalyze 14 index patients/families who remained without genetic diagnosis by WES. We were able to identify the genetic cause of HL in 6 families (43 %). Two families were diagnosed with DFNB84A caused by compound heterozygous recessive mutations in PTPRQ. Three of the four underlying variants, including a structural variant, a deep intronic variant, and a splice variant, escaped detection by WES. Minigene assays confirmed the pathogenicity of the intronic and the splice variants. In addition, we used protein 3D structure prediction and rigid ligand docking to study the pathogenicity of variants that escape nonsense-mediated decay. CONCLUSION: In our study, we present four novel variants in PTPRQ, three of which were detected only by WGS. To our knowledge, we report here the first pathogenic deep intronic PTPRQ variant causing HL. Our results suggest that the mutational spectrum of PTPRQ is not well covered by standard WES and that PTPRQ-associated hearing loss may be more frequent than previously thought. WGS provides an additional layer of information in the diagnostics of HL.

Humans↗

PubMed2006

Identification and functional analysis of common human flavin-containing monooxygenase 3 genetic variants.

Flavin-containing monooxygenases (FMOs) are important for the disposition of many therapeutics, environmental toxicants, and nutrients. FMO3, the major adult hepatic FMO enzyme, exhibits significant interindividual variation. Eighteen FMO3 single-nucleotide polymorphism (SNP) frequencies were determined in 202 Hispanics (Mexican descent), 201 African Americans, and 200 non-Latino whites. Using expressed recombinant enzyme with methimazole, trimethylamine, sulindac, and ethylenethiourea, the novel structural variants FMO3 E24D and K416N were shown to cause modest changes in catalytic efficiency, whereas a third novel variant, FMO3 N61K, was essentially devoid of activity. The latter variant was present at an allelic frequency of 5.2% in non-Latino whites and 3.5% in African Americans, but it was absent in Hispanics. Inferring haplotypes using PHASE, version 2.1, the greatest haplotype diversity was observed in African Americans followed by non-Latino whites and Hispanics. Haplotype 2A and 2B, consisting of a hypermorphic promoter SNP cluster (-2650C>G, -2543T>A, and -2177G>C) in linkage with synonymous structural variants was inferred at a frequency of 27% in the Hispanic population, but only 5% in non-Latino whites and African Americans. This same promoter SNP cluster in linkage with one or more hypomorphic structural variant also was inferred in multiple haplotypes at a total frequency of 5.6% in the African-American study group but less than 1% in the other two groups. The sum frequencies of the hypomorphic haplotypes H3 [15,167G>A (E158K)], H5B [-2650C>G, 15,167G>A (E158K), 21,375C>T (N285N), 21,443A>G (E308G)], and H6 [15,167G>A (E158K), 21,375C>T (N285N)] was 28% in Hispanics, 23% in non-Latino whites, and 24% in African Americans.

Black or African American↗

PubMed1994

Biological activities and secondary structures of variant forms of human salivary cystatin SN produced in Escherichia coli.

Using an Escherichia coli expression system, pGEX-2T, that expresses foreign sequences as fusion proteins with a glutathione S-transferase (GST) carrier, we have produced several recombinant human salivary cystatin SN (reCsnSN) variants. These include a N-terminal-truncated form (aa 17-121), a C-terminal-truncated form (aa 1-102) and two deletion mutants (delta 12-16 and delta 56-60). A large amount of the insoluble fusion protein (approx. 15 mg/l) was produced in each case. These were solubilized with urea and refolded by dialysis. The GST carrier was then cleaved with thrombin and the reCsn variants (except delta 56-60) were purified by anion-exchange chromatography. The CysP inhibitory activities against papain, and bovine and human cathepsin B, and secondary structures of the reCsnSN variants were determined and compared to natural salivary CsnSN. The full-length reCsnSN, the N-truncated and the delta 12-16 variants inhibited the CysP activity of papain and displayed circular dichroism (CD) spectra similar to that of natural CsnSN. On the other hand, the delta 56-60 mutant and the C-truncated variant exhibited very little inhibitory activity towards papain. The CD spectrum of the C-truncated variant indicated a change in the secondary structure (e.g., a decrease in beta-sheet and an increase of an alpha-helical content). Neither, the natural nor the full-length reCsnSN or the delta 12-16 mutant exhibited any inhibitory activity towards bovine and human cathepsin B.

Amino Acid Sequence↗

PubMed2026

Small Copy Number Neutral Intrachromosomal Translocation of PAX6 and Aniridia.

IMPORTANCE: Approximately 5% to 10% of individuals with classic aniridia do not receive a molecular diagnosis after clinical testing for variants in PAX6 and its downstream regulatory region. OBJECTIVE: To apply optical genome mapping (OGM) and long-read whole-genome sequencing (lrWGS) to diagnose an individual with unexplained classic aniridia. DESIGN, SETTING, AND PARTICIPANTS: High-quality DNA was extracted from the blood of a 16-year-old male patient with classic aniridia and prior negative clinical test results that included sequencing and copy number analysis of PAX6 exons and downstream regulatory region as well as genomic analysis via short-read whole-genome sequencing (srWGS) and analyzed using OGM and lrWGS. All analyses were performed in a research laboratory in Wisconsin from January 2019 to September 2025. INTERVENTIONS: OGM and lrWGS. MAIN OUTCOMES AND MEASURES: Identification of a structural variant disrupting PAX6 expression in an individual with classic aniridia, following negative prior testing including srWGS. RESULTS: OGM identified a 55-kb deletion on 11p13 encompassing all PAX6 exons and exon 12 of ELP4, with insertion of this segment into 11q21. lrWGS delineated the exact breakpoints, confirming that the downstream regulatory region, required for normal PAX6 expression, remained at the 11p13 locus. Consequently, the translocated copy of PAX6 at 11q21 is expected to lack expression due to the loss of its essential regulatory elements. CONCLUSIONS AND RELEVANCE: These findings in an individual with classic aniridia harboring an intrachromosomal rearrangement at the PAX6 locus identified by OGM and lrWGS may represent the smallest reported structural variant to separate the PAX6 coding sequence from its downstream regulatory region. This structural variant may have fallen below the detection threshold of srWGS due to its balanced nature and small size, suggesting OGM and lrWGS would be needed for definitive identification.

Aniridia↗

PubMed1981

Inhibitor studies of phage T4 wild-type and mutant DNA polymerases. V. A. summary of kinetic and inhibitor data.

The DNA polymerases of phage T4 wild-type, the mutator mutant L98 and the antimutator mutant CB121 were purified about 100-fold free of foreign enzyme activities interfering with the polymerase assay. The enzymes were characterized as to thermostability, exonuclease activity and kinetic data with DNA template primer, deoxythymidine 5' -triphosphate, and a mixture of all four deoxynucleoside 5' -triphosphates. The effects of eight inhibitors of DNA synthesis on the three enzymes were determined (Schroeder and Jantschak 1978 and 1980, Jantschak and Schroeder 1980) and are compared here. The most selective inhibitor, pyridoxal 5' -phosphate, interacts with the active site of the polymerases while the two least discriminating drugs, distamycin A and actinomycin D, do not directly interact with the polymerases at all. The study was intended to test whether specific enzyme inhibitors elicit a differential response in temperature-sensitive structural variants of this enzyme and whether, in principle, structural variants of virus enzymes or the respective ts- mutants in vivo are suitable as a screening system for selective antiviral agents.

DNA-Directed DNA Polymerase↗

PubMed2005

Fine-scale structural variation of the human genome.

Inversions, deletions and insertions are important mediators of disease and disease susceptibility. We systematically compared the human genome reference sequence with a second genome (represented by fosmid paired-end sequences) to detect intermediate-sized structural variants >8 kb in length. We identified 297 sites of structural variation: 139 insertions, 102 deletions and 56 inversion breakpoints. Using combined literature, sequence and experimental analyses, we validated 112 of the structural variants, including several that are of biomedical relevance. These data provide a fine-scale structural variation map of the human genome and the requisite sequence precision for subsequent genetic studies of human disease.

Base Pairing↗

PubMed1991

Secretion and in vivo folding of the Fab fragment of the antibody McPC603 in Escherichia coli: influence of disulphides and cis-prolines.

Using the well-characterized antibody McPC603 as a model, we had found that the Fv fragment can be isolated from Escherichia coli as a functional protein in good yields, whereas the amount of the correctly folded Fab fragment of the same antibody produced under identical conditions is significantly lower. In this paper, we analyse the reasons for this difference. We found that a variety of signal sequences function in the secretion of the isolated chains of the Fab fragment or in the co-secretion of both chains in E.coli. The low yield of functional Fab fragment is not caused by inefficient expression or secretion in E.coli, but by inefficient folding and/or assembly in the periplasm. We compared the folding yields for the Fv and the Fab fragment in the periplasm under various conditions. Several diagnostic framework variants were constructed and their folding yields measured. The results show that substitutions affecting cis-proline residues and those affecting various disulphide bonds in the protein are by themselves insufficient to dramatically change the partitioning of the folding pathway to the native structure, and the cause must lie in a facile aggregation of folding intermediates common to all structural variants. However, all structural variants could be obtained in native form, demonstrating the general utility of the secretory expression strategy.

Amino Acid Sequence↗

PubMed2003

Identification of novel variants of the flavin-containing monooxygenase gene family in African Americans.

Sequence polymorphisms in enzymes involved in drug metabolism have been widely implicated in the differences observed in the sensitivity to various xenobiotics. The flavin-containing monooxygenase (FMO) gene family in humans catalyzes the monooxygenation of numerous N-, P- and S-containing drugs, pesticides, and environmental toxicants. Six genes (FMO1-6) have been identified so far, but the major alleles of FMO2 and FMO6 encode nonfunctional proteins due to a nonsense mutation and splice-site abnormalities, respectively. Data on structural variants exist for human FMO2 and 3, whereas very little is known about the other FMO genes. FMO1-6 were scanned in 50 individuals of African-American descent using the method, detection of virtually all mutations-single-strand conformational polymorphism. A total of 49 sequence variants were identified in a total 1.35 megabases of scanned sequence, of which 29 were variants affecting protein structure or expression. Some of these are expected to affect the activity of the protein, including a nonsense mutation in FMO1 (R502X) and missense mutations in FMO1 (I303T), FMO4 (E339Q), and FMO5 (P457L) that occur in highly conserved amino acids. Additional deleterious substitutions in FMO2 (del337G) and FMO6 (Q105X) were also identified. Multiple structural variants in the FMO gene family were observed in this African-American sample. Some of the substitutions identified in this study might be useful markers in future association studies assessing sensitivity to environmental toxicants and common disease.

Black or African American↗

PubMed2004

Genomic organization of the mouse Msh4 gene producing bicistronic, chimeric and antisense mRNA.

By degenerate PCR and screening of mouse testis cDNA library, we have identified seven cDNAs from the meiotic recombination gene Msh4. Variant alpha and probably beta are likely involved in meiotic DNA recombination. Other variants have distinctive structures; variant epsilon, theta; and iota form a bicistronic operon, while variant delta contains antisense RNA for the endoplasmic reticulum (ER) chaperon Hspa5 gene and small open reading frame (ORF) identical to epsilon ORF2. Analysis of the exon-intron structures revealed unusual genomic organizations: the first three exons of delta and the first exon of epsilon are respectively mapped to the Hspa5 locus on chromosome 2 and the Pcbp3 locus on chromosome 10; the remaining exons of both variants are mapped to the Msh4 locus on chromosome 3. The first exon of variant beta is located on chromosome 16, while the others are located on chromosome 3. Synthesis of these mRNAs is assumed to require interchromosomal trans-splicing alone (beta and epsilon) or in combination with converse-splicing (delta). Most Msh4 variant mRNAs are mainly expressed in testis, but a small amount of each variant except for epsilon is also expressed in brain, heart, thymus, ovary and embryonic head. Enhanced green fluorescent protein (EGFP) fusion experiments showed that all the ORFs are translated, and most of those proteins are localized to a particular subcellular compartment. It also appeared that expression of variant delta induces cell death. This study suggests that the dynamic interchromosomal (intergenic) trans-splicing generates functional diversity of the mouse Msh4 gene.

Alternative Splicing↗

PubMed2003

Mannose-binding lectin deficiency--revisited.

There is an emerging interest for mannose-binding lectin (MBL) due to its role in innate immunity. In this survey we present a mixture of old and new data describing the effect MBL polymorphisms may have on the level and function of the molecule. Three single nucleotide substitutions in exon 1 of the mbl2 gene cause a dominant decrease of functional MBL in the circulation. Additionally, promoter variants influence expression of MBL. It has been assumed that the structural variant alleles may disrupt the assembly of MBL trimers or accelerate the degradation of the protein, thereby causing the decrease in MBL serum concentrations. We have analysed 1183 different sera in a double sandwich antibody ELISA using the same antibody to capture and detect MBL and find the same results as have been presented previously showing that different MBL promoter alleles have profound effect of on the MBL serum concentration. The use of a new anti-MBL monoclonal antibody, however, has shown that the amount of MBL in the circulation is less dependent on the presence of structural variant alleles than previously anticipated. Molecular characterisation of MBL revealed that sera from donors homozygous for the normal MBL genotype predominantly contained high molecular weight MBL, while sera from individuals heterozygous for the variant alleles contained both high and low molecular weight MBL. The ratio between high and low molecular weight MBL was dependent on the MBL promoter type on the normal haplotype. Sera deriving from individuals homozygous for MBL variant alleles contained mainly low molecular weight MBL. Of the different oligomers of MBL only the high molecular weight forms bound mannan efficiently and activated complement. In contrast to a previous notion, we demonstrate that variant alleles give rise to relatively high levels of MBL in the circulation. However, the variant MBL has lower molecular weight and is dysfunctional compared to normal MBL. The physiological relevance of variant MBL remains to be established.

Alleles↗

PubMed2026

Expansion of the allelic and phenotypic spectrum of MED25-related developmental disorder: novel compound heterozygous variants with structural domain implications.

MED25-related developmental disorder (Basel-Vanagaite-Smirin-Yosef syndrome) is a rare autosomal recessive disorder, defined by severe neurodevelopmental delay, corpus callosum abnormalities, ocular involvement, epilepsy, and marked facial appearance. MED25 pathogenic variants interfere with the functioning of the Mediator complex, which is responsible for RNA polymerase II transcription. We report a 9-year-old girl who presents with significant global developmental delay, agenesis of the corpus callosum, congenital cataracts, epilepsy, hypotonia, musculoskeletal abnormalities, and typical craniofacial features. Trio-based whole-exome sequencing revealed compound heterozygous variants in MED25: a maternally transmitted truncating variant (c.1366 C > T; p.Gln456*) and a paternally inherited missense variant (c.430 C > T; p.Leu144Phe). The new classification of the missense variant as potentially pathogenic is supported by a systematic ACMG re-evaluation supported by segregation analysis, phenotypic specificity, computational prediction, and structural localization in the MED25 Activator Interaction Domain (ACID). Comparative phenotypic analyses show strong agreement with reported cases but add more data to fine-tune clinical spectrum. This article broadens the allelic and phenotypic spectrum of MED25-related developmental disorder and highlights the need for comprehensive evaluation across molecular, structural, and phenotypic pathways to elucidate variant signature in rare genetic disease models correctly.

Humans↗

PubMed1980

Inherited structural polymorphism of the fourth component of human complement.

Human fourth component of complement (C4) was found to be highly polymorphic by agarose gel electrophoresis of neuraminidase-treated plasma. The system allows clear-cut separation of the products of the two C4 genetic loci, C4A (acidic or Rodgers) and C4B (basic or Chido). There are at least six structural variants and a deletion allele at the C4A locus and two structural variants and a deletion allele at the C4B locus. Close linkage with no crossovers was found between the two C4 loci, allowing the definition of C4AB haplotypes, and between C4 haplotypes and the C2 and BF loci of the human histocompatibility complex. Nine C4 haplotypes, each with a frequency of 0.005 or more in Caucasians, were found. These studies provide direct evidence for two distinct but closely linked genetic loci for human C4 in the major histocompatibility complex on the short arm of chromosome 6.

Alleles↗