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PubMed2004

Molecular variants of the sodium/hydrogen exchanger type 3 gene and essential hypertension.

OBJECTIVES: The objectives of this study were to identify polymorphic variants within the gene coding for the sodium/hydrogen exchanger type 3 (NHE3) and to examine their relationship with hypertension and biochemical indices of sodium balance. DESIGN AND METHODS: Case-control comparisons on a total of 691 subjects of which 399 (68% with essential hypertension) were of African or Afro-Caribbean origin (blacks) and 292 (50% with essential hypertension) were of Caucasian origin (whites). RESULTS: Eight exons of the C terminus of the NHE3 gene were screened systematically. A total of six variants were identified: (G1579A, G1709A, G1867A, C1945T, A2041G and C2405T). Further analyses in relation to essential hypertension and phenotypic characteristics were confined to the more frequent A2041G and the C2405T polymorphisms. The genotype frequencies of the A2041G polymorphism were significantly different between the whites and blacks, with the A allele being more frequent in the white population (0.43 for the whites and 0.14 for the blacks, respectively; P < 0.001). In contrast, there was no significant difference in the C2405T polymorphism between whites and blacks (C allele frequency: 0.86 for the whites and 0.88 for the blacks, respectively). In both the white and the black groups, there were no significant associations between these variants and essential hypertension (P > 0.05) or with serum electrolytes, creatinine or plasma renin activity (PRA) (ANOVA P > 0.05). CONCLUSIONS: These results suggest a high degree of structural conservation of the NHE3 gene; however, the lack of association between these polymorphisms and blood pressure status does not necessarily eliminate the participation of this important sodium/hydrogen exchanger in the pathophysiology of essential hypertension, as we cannot exclude the existence of functionally important genetic variants in other sequences within the NEH3 gene.

Adult↗
PubMed2003

Detailed analysis of allelic variation in the ABCA4 gene in age-related maculopathy.

PURPOSE: Age-related maculopathy (ARM) is one of the most common causes of blindness in older adults worldwide. Sequence variants in a gene coding for a retina-specific ATP-binding cassette (ABCA4) transporter protein, which is responsible for a phenotypically similar Mendelian form of retinal disease, were proposed to increase the risk of ARM. To examine the potential relationship of ABCA4 sequence variation and ARM risk in an independent data set, a clinically well-characterized population of 165 multiplex patients with ARM from 70 families, 33 unaffected relatives, and 59 unrelated control subjects with confirmed absence of ARM was screened for variants in any of the 50 exons and exon-intron boundaries of this gene. METHODS: A combination of denaturing high-performance liquid chromatography (DHPLC) and bidirectional sequencing was used to detect ABCA4 sequence variants. The data set was analyzed with both case-control and family-based association analysis methods. RESULTS: No evidence was found of significantly different allele frequencies of ABCA4 sequence variants in patients compared with control subjects, and no evidence for association or cosegregation with disease in family-based analyses. CONCLUSIONS: This study confirmed the very high degree of ABCA4 sequence polymorphism in the general population, which makes the detection of potential disease-associated alleles particularly challenging. While this study does not definitively exclude ABCA4 from contributing to a small or moderate fraction of ARM, it adds to the body of evidence suggesting that ABCA4 is not a major susceptibility gene for this disorder.

ATP-Binding Cassette Transporters↗
PubMed1979

Alleles of the fibroin gene coding for proteins of different lengths.

Bombyx mori silkworms producing fibroin proteins of different lengths have been analyzed genetically and shown to possess variant alleles of a single fibroin gene. The structures of two alleles have been compared by using restriction endonuclease sites inside and outsite the fibroin gene as physical markers. We find that fibroins distinguishable on the basis of length are encoded by genes with different internal structures and overall lengths. Our results strongly support the idea that rearrangements within the highly repetitive sequences of the fibroin gene are the result of unequal recombination, and can give rise to variant fibroin genes with altered coding lengths.

Alleles↗
PubMed2006

Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population.

BACKGROUND: Chinese and Malay subjects have been reported to require less maintenance warfarin than Indians that could not be accounted for by cytochrome P450 (CYP) 2C9 variants. Vitamin K epoxide reductase complex 1 (VKORC1) is the target enzyme of warfarin, and VKORC1 intronic variants and haplotypes have recently been shown to influence VKORC1 activity and warfarin requirements. METHODS: We sequenced the coding regions of CYP2C9 and VKORC1 and inferred VKORC1 haplotype from 10 intronic variants in 147 Chinese, 85 Malay, and 43 Indian patients receiving maintenance warfarin. RESULTS: The mean weight-normalized warfarin dose was lower for Chinese and Malays than for Indians (0.058 +/- 0.025 mg/kg, 0.059 +/- 0.023 mg/kg, and 0.089 +/- 0.036 mg/kg, respectively; P < .001 for comparisons between Chinese and Malays with Indians). CYP2C9*2 and VKORC1 coding region variants were rare (<2%), whereas CYP2C9*3 associated with lower warfarin requirements was less common in Chinese and Malays (7% and 9%, respectively) than in Indians (18%) and could not account for their lower warfarin requirements. VKORC1 H1 and H7/H8/H9 haplotypes were associated with lower and higher warfarin requirements, respectively (0.050 +/- 0.019 mg/kg and 0.092 +/- 0.057 mg/kg, respectively; P < .001). VKORC1 H1 haplotype (requiring low warfarin doses) was common in Chinese (87%) and Malays (65%) but uncommon in Indians (12%), whereas H7, H8, and H9 haplotypes (requiring high warfarin doses) were rare in Chinese (9%), intermediate in Malays (30%), and common in Indians (82%). The interethnic difference in warfarin requirements became nonsignificant when adjusted for VKORC1 haplotype. CONCLUSIONS: Interethnic difference in VKORC1 haplotypes accounts for the difference in warfarin requirements between Chinese, Malays, and Indians, providing interesting insights into genetic variation between ethnogeographically distinct Asian groups.

Anticoagulants↗
PubMed2001

A unique exonic splicing mutation in the human androgen receptor gene indicates a physiologic relevance of regular androgen receptor transcript variants.

In a patient with partial androgen insensitivity syndrome (AIS), we identified a single inherited presumably silent nucleotide variation (AGC -> AGT) in exon 8 (codon 888) of the AR gene. However, in the patient's genital skin fibroblasts, a considerably shortened transcript of 5.5 kb (normal: 10.5 kb) was detected, which misses a part of exon 8 and a prominent portion of the 3'-untranslated region. The translation product includes eight missense amino acids from codon 886 onward followed by a premature stop codon. As shown by in vitro expression analysis, the mutant protein lacks any residual function. However, reverse transcribed PCRs and sequence data indicate the existence of two additional splicing variants of 6.4 kb and 7.8-kb length both in patient and normal control genital skin fibroblasts. These splicing variants comprise the complete coding region but a shortened 3'-untranslated region. Thus, a distinct alternative pre-messenger RNA-processing event leading to two additional transcripts occurs generally in genital skin fibroblasts. In addition, this process partially prevents aberrant splicing in the patient and produces a small fraction of normal, functionally intact AR-protein that could explain the partial masculinization in this patient. This first report of an exonic splicing mutation in the AR-gene indicates a physiologic relevance of the regular AR-messenger RNA variants with shortened 3'-untranslated regions and their functional translation products in human genital development.

3' Untranslated Regions↗
PubMed2004

Identification of paraoxonase 3 gene (PON3) missense mutations in a population of southern Italy.

PON gene family includes at least three members termed PON1, PON2 and PON3, and it is mapped on human chromosome 7q21-q22. PON1 and PON3 gene products are constituents of high density lipoprotein (HDL) and have many enzymatic properties and antioxidant activity. PONs are proposed to participate in the prevention of low density lipoprotein (LDL) oxidation. PON1 and PON2 genes have missense polymorphisms, but, to date, no missense variants are reported in PON3 gene. In this work we explored the existence of genetic variants within the PON3 coding sequences. Five point mutations were identified by direct sequencing of genomic DNA derived from 250 randomly selected DNA samples of 1143 blood donors living in southern Italy. Three were silent mutations, while two were missense mutations that give rise to amino acid substitutions at positions 311 (S>T) and 324 (G>D). The missense variations in the DNA of the 1143 samples had frequencies of 0.22% (5 out of 2286 alleles) for the S311T mutation, and 0.57% (13 out of 2286 alleles) for the G324D mutation. The effect of these variants on the metabolic activity of paraoxonase 3 remains to be further evaluated.

Alleles↗
PubMed2006

Improving gene annotation using peptide mass spectrometry.

Annotation of protein-coding genes is a key goal of genome sequencing projects. In spite of tremendous recent advances in computational gene finding, comprehensive annotation remains a challenge. Peptide mass spectrometry is a powerful tool for researching the dynamic proteome and suggests an attractive approach to discover and validate protein-coding genes. We present algorithms to construct and efficiently search spectra against a genomic database, with no prior knowledge of encoded proteins. By searching a corpus of 18.5 million tandem mass spectra (MS/MS) from human proteomic samples, we validate 39,000 exons and 11,000 introns at the level of translation. We present translation-level evidence for novel or extended exons in 16 genes, confirm translation of 224 hypothetical proteins, and discover or confirm over 40 alternative splicing events. Polymorphisms are efficiently encoded in our database, allowing us to observe variant alleles for 308 coding SNPs. Finally, we demonstrate the use of mass spectrometry to improve automated gene prediction, adding 800 correct exons to our predictions using a simple rescoring strategy. Our results demonstrate that proteomic profiling should play a role in any genome sequencing project.

Algorithms↗
PubMed1993

Novel hirudin variants from the leech Hirudinaria manillensis. Amino acid sequence, cDNA cloning and genomic organization.

Novel hirudin variants isolated from the leech Hirudinaria manillensis, a leech more specialized for mammalian parasitism, are described. Isolation of antithrombin polypeptides was performed by ion-exchange chromatographies followed by an affinity chromatography step on immobilized thrombin. The major active component, antithrombin polypeptide peak 2 (HM2) and a second polypeptide, named HM1, were purified to homogeneity and their complete amino acid sequences were determined. The protein structure of the two hirudin variants include 64 amino acids with 6 cysteine residues at highly conserved positions. Comparison of the amino acid sequences of HM1 and HM2 with other known hirudins shows differences mainly in the central part and in the C-terminal region of the polypeptides. Particularly significant is the lack of a sulfated tyrosine residue in the C-terminal portion of the molecule which is replaced by aspartic acid. Polymerase chain reaction cloning techniques were used to isolate and characterize the cDNAs and determine the genomic structures of these hirudin-like polypeptides. The cDNA clones coding for the two variants indicate the expression of pre-hirudins of 84 amino acids where the first 20 residues constitute the signal peptide required for extracellular secretion. The leader sequence appears to be highly conserved for both isoforms and shares a complete similarity with the partial hirudin variant 2 (HV2) signal peptide sequence previously reported. The HM1 and HM2 gene fragments show the presence of four exons: the first one corresponding to a 20-amino-acid signal peptide while the other three exons share the full primary structure of the antithrombin polypeptides. HM2 was also efficiently produced in recombinant Escherichia coli by expressing a periplasmic construction containing the synthetic gene.

Amino Acid Sequence↗
PubMed2004

Crustacean retinoid-X receptor isoforms: distinctive DNA binding and receptor-receptor interaction with a cognate ecdysteroid receptor.

We have identified cDNA clones that encode homologs of the ecdysteroid receptor (EcR) and retinoid-X receptor (RXR)/USP classes of nuclear receptors from the fiddler crab Uca pugilator (UpEcR and UpRXR). Several UpRXR cDNA splicing variants were found in coding regions that could potentially influence function. A five-amino acid (aa) insertion/deletion is located in the "T" box in the hinge region. Another 33-aa insertion/deletion is found inside the ligand-binding domain (LBD), between helix 1 and helix 3. Ribonuclease protection assays (RPA) showed that four UpRXR transcripts [UpRXR(+5+33), UpRXR(-5+33), UpRXR(+5-33) and UpRXR(-5-33)] were present in regenerating limb buds. UpRXR(-5+33) was the most abundant transcript present in regenerating limb buds in both early blastema and late premolt growth stages. Expression vectors for these UpRXR variants and UpEcR were constructed, and the proteins expressed in E. coli and in vitro expression systems. The expressed crab nuclear receptors were then characterized by electrophoretic mobility shift assay (EMSA) and glutathione S-transferase (GST) pull down experiments. EMSA results showed that UpEcR/UpRXR(-5+33) heterocomplexes bound with a series of hormone response elements (HREs) including eip28/29, IRper-1, DR-4, and IRhsp-1 with appreciable affinity. Competition EMSA also showed that the affinity decreased as sequence composition deviated from a perfect consensus element. Binding to IRper-1 HREs occurred only if the heterodimer partner UpRXR contained the 33-aa LBD insertion. UpRXR lacking both the 5-aa and 33-aa insertion bound to a DR-1G HRE in the absence of UpEcR. The results of GST-pull down experiments showed that UpEcR interacted only with UpRXR variants containing the 33-aa insertion, and not with those lacking the 33-aa insertion. These in vitro receptor protein-DNA and receptor protein-protein interactions occurred in the absence of hormone (20-hydroxyecdysone and 9-cis retinoid acid, 9-cis RA). Transactivation studies using a hybrid UpEcR ligand-binding domain construct and UpRXR (+/-33) ligand-binding domain constructs also showed that the 33-aa insertion was indispensable in mediating ecdysteroid stimulated transactivation.

Alternative Splicing↗
PubMed2006

A gene-to-gene interaction between aromatase and estrogen receptors influences bone mineral density.

OBJECTIVE: The aromatization of androgenic precursors is the main source of estrogens in postmenopausal women. We tested the hypothesis that allelic variants of the genes coding for aromatase and estrogen receptors (ER) could interact to determine the estrogenic signals on the bone tissue and, consequently, bone mineral density (BMD). DESIGN: Cross-sectional study including 331 postmenopausal women. METHODS: BMD was measured by dual energy x-ray absorptiometry. A CG polymorphism of the aromatase gene as well as three polymorphisms of ERalpha (a TA repeat in the promoter region, a C T single nucleotide polymorphism (SNP) in intron 1 and an AG SNP in exon 8) and a CA repeat polymorphism of ERbeta were studied. RESULTS: Age, body weight and the aromatase genotype were associated with BMD. Allelic variants of ERbeta and the exon 8 of ERalpha did not show a significant association with BMD. The polymorphisms located on the promoter and intron 1 of ERalpha interacted strongly with aromatase. Thus, in women TT homozygous for the ERalpha gene, there was a marked influence of aromatase genotypes on BMD: spine BMD was 0.724 +/- 0.027 g/cm2 in women with CC aromatase alleles and 0.926 +/- 0.032 g/cm2 in those with GG alleles (P < 0.001). Hip BMD in women with CC and GG aromatase genotypes was 0.722 +/- 0.020 and 0.842 +/- 0.026 g/cm2 respectively (P = 0.002). On the contrary, there were no aromatase-related differences in BMD in women with CT/CC alleles of ERalpha. Similarly, aromatase-related differences in BMD were found in women with short alleles at the promoter region of ERalpha, but not in those with long alleles. Both ERalpha polymorphisms were in strong linkage disequilibrium (P < 0.001). CONCLUSION: These results suggest that the interaction between polymorphisms of genes involved in estrogen synthesis and estrogen signaling exerts an important influence on BMD in postmenopausal women, thus helping to explain, in part, its heritable component. Nevertheless, further studies are warranted to confirm this gene-to-gene interaction in other populations.

Absorptiometry, Photon↗
PubMed1986

Generation of transgenic mice producing a human transthyretin variant: a possible mouse model for familial amyloidotic polyneuropathy.

Type I familial amyloidotic polyneuropathy (FAP) results from the systemic deposition of a plasma transthyretin (TTR) variant with a Val----Met change at position 30. In an attempt to establish a model of this disease, we generated transgenic mice producing the variant TTR. A DNA fragment containing the mouse metallothionein-I promoter fused to the structural gene coding for the human TTR variant was microinjected into fertilized mouse eggs. Among 72 mice that developed from these eggs, ten carried the fusion gene and three of these showed significant concentrations of the variant TTR in their serum. These mice may be useful in elucidating the pathogenesis of FAP and in establishing a therapy for this intractable disorder.

Animals↗
PubMed1983

Histone mRNA concentrations are regulated at the level of transcription and mRNA degradation.

The levels of histone mRNA are rapidly reduced after treatment of cultured cells with hydroxyurea or cytosine arabinonucleoside. The histone mRNA for the replicative histone variants is destroyed rapidly, with a half-life of 10-15 min. The levels of mRNA coding for the replacement histone variant H3.3 were unchanged after treatment with DNA synthesis inhibitors. In addition to the rapid destruction of histone mRNA, there was a reduction to 1/5th in the rate of transcription of the histone genes. Lymphoma cells (S49) arrested in G1 by cyclic AMP produce and contain significant levels of histone mRNA. Hydroxyurea reduces the rate of transcription and the levels of histone mRNA in the G1-arrested cells.

Animals↗
PubMed1999

Neutral sequence variants and haplotypes at the 150 Kb ataxia-telangiectasia locus.

Sequence variants occur every few hundred bases in the human genome. We evaluated the relationship between disease-causing mutations and neutral sequence variants at the 150 Kb ataxia-telangiectasia (A-T) locus. Mutations at this locus cause a distinct autosomal recessive syndrome in homozygotes and predispose heterozygotes to cancer and coronary heart disease. Nine common neutral sequence variants were observed in the coding and splice junction regions of 132 chromosomes from Caucasian individuals of European origin. Each of these variants appeared frequently in both A-T and non-A-T chromosomes. However, there was remarkable linkage disequilibrium between the polymorphic loci, resulting in only 7 haplotypes in analyzed chromosomes. These 7 haplotypes fell into 3 major ancestral groups. No individual polymorphic variant or haplotype correlated reliably with the presence of an A-T mutation. Thus, comparing the frequency of neutral variants at the A-T locus in diseased and non-diseased populations is unlikely to uncover the relationship of mutations at this locus to common diseases. These data reflect general limitations on using single nucleotide polymorphisms (SNPs) to identify loci for many common diseases.

Alleles↗
PubMedDate not supplied

Synthesis and expression of mRNA encoding for different versican splice variants is related to the aggregation of human epithelial mesothelioma cells.

Malignant mesothelioma often has a biphasic growth pattern of epithelial and/or sarcomatous morphology. In culture, epithelial cells form aggregates, whereas fibroblast-like cells do not. Two human mesothelioma cell sub-lines, one with epithelial differentiation and the other with fibroblast-like phenotype were studied. We have previously shown (Dobra et al, 2000) that distinct types of the cell-associated syndecans are involved in the regulation of mesothelioma cell differentiation, whereas the role of matrix proteoglycans (PGs) remains unknown. This study was undertaken to examine whether cell aggregation of the epithelial mesothelioma cells correlates to the differential expression of the matrix PGs versican and perlecan at different degrees of confluence. PGs were isolated from the culture medium using ion-exchange chromatography and identified by high-performance liquid chromatography, capillary electrophoresis and Western blotting. Fibroblast-like cells express substantially more versican than epithelial cells. RT-PCR showed that both cell lines express mRNA coding for versican splice variants V0 and V1, but not for V2. The dominating splice variant in both cell lines is the V0. Screening of versican splice variants in various degrees of culture confluence showed that the expression of mRNA conding for the versican splice variants V0 and V1 is different only in confluent cultures. No significant differences in the expression of perlecan between the two cell lines were recorded. These results suggest that the aggregation of epithelial cells is related to a significant decrease (p < or = 0.001) of the splice variant V1. This variant seems to be a biologically active constituent that affects tumor biology.

Alternative Splicing↗
PubMed1986

Mutational analysis of DNA sequences affecting the replication of defective polyomavirus variant D-50.

The genome of the defective polyomavirus variant D-50 consists of tandemly repeated DNA segments. The repeat unit corresponds to a 17% fragment of polyomavirus DNA (Griffin and Fried (1975) Nature 256, pp. 175-179). To allow mutational analysis, a monomer unit of D-50 DNA was cloned. After excision from the plasmid and ligation to form a random mixture of products, circular head to tail oligomers of the cloned segment were replicated in transfected cells. Those molecules had the same replication properties as original D-50 DNA. Deletion of base sequences assumed to be at the origin of DNA synthesis inhibited the replication completely, whereas a deletion of a segment at the junction of the tandem repeats had only a slight inhibitory effect. Mutation of potential coding sequences of the variant genome had a slight stimulatory effect on DNA synthesis, ruling out that D-50 expresses any protein that stimulates replication. In an attempt to construct variants similar to D-50, cells were transfected with polyomavirus DNA fragments including the sequences of the D-50 monomer unit. However, all these molecules replicated very slowly, suggesting the presence of an element that inhibited DNA synthesis. The combined data show that D-50 genomes can be reconstituted by ligation of monomer units and that the origin of DNA replication was the only essential element of the variant genome, whereas other elements had cis-acting auxiliary functions.

Base Sequence↗
PubMed2005

Molecular evaluation of CFTR sequence variants in male infertility of testicular origin.

Although the involvement of the CFTR gene has been well established in congenital agenesia of vas deferens, its role in non-obstructive (NOb) infertility is still a matter of debate. In order to definitively define the involvement of the CFTR gene in spermatogenic impairment and a potential synergistic contribution to known genetic and clinical factors, genetic variants in the entire coding sequence and the immediately flanking regions of the CFTR gene, along with a thorough clinical evaluation, were analysed in 83 NOb infertile patients and 87 clinically well-defined fertile individuals as controls. The results of our study showed no statistical difference between CFTR carrier frequency in the infertile and fertile population. Specifically, the IVS8-6(5T) allele carrier frequency was similar in NOb infertile patients when compared with fertile men, but it is noteworthy that, when fertile men were classified into having optimal and suboptimal fertility, no 5T allele was found among the 35 men with optimal fertility parameters. In conclusion, extensive CFTR analysis in infertile individuals and fertile population as adequate control definitively excludes the involvement of the CFTR gene variants in sperm production and stresses the importance of carefully identifying those individuals with obstructive defects, in whom CFTR screening will be beneficial.

Base Sequence↗
PubMed1997

Vascular endothelial growth factor up-regulates its receptor fms-like tyrosine kinase 1 (FLT-1) and a soluble variant of FLT-1 in human vascular endothelial cells.

The growth of solid tumors and the formation of metastases are dependent on neoangiogenesis. One of the most important factors in inducing the formation of new blood vessels is the vascular endothelial growth factor (VEGF), which acts specifically on endothelial cells. VEGF is expressed and secreted by almost all solid tumors. The molecular mechanisms leading to enhanced production of this angiogenic mitogen are manyfold and have been elucidated to some degree. Two VEGF receptors, fms-like tyrosine kinase 1 (FLT-1) and KDR, have been identified almost specifically on human endothelial cells. They are expressed preferentially in the proliferating endothelium of vessels lining and/or penetrating solid tumors, whereas they are almost undetectable by convenient methods in vessels of healthy tissue. However, the underlying mechanisms are not understood. We could show that media conditioned by various cancer cell lines grown under hypoxic conditions were able to up-regulate expression of FLT-1 mRNA and protein but not of KDR mRNA. Furthermore, up-regulation of a shorter mRNA species was observed that most probably codes for the soluble variant of FLT-1. These effects were completely inhibited by VEGF-neutralizing extracellular VEGF receptor domains. The effect could be mimicked by adding recombinant VEGF instead of conditioned cancer cell medium to the endothelial cell cultures. Both mutant VEGF, which activates only KDR, and placenta growth factor, which activates only FLT-1, were able to enhance FLT-1 expression. VEGF-stimulated FLT-1 mRNA expression was inhibited by actinomycin D. These data suggest that VEGF itself is the main factor secreted by tumor cells that is able to enhance the expression of its receptor FLT-1 and of a soluble variant of FLT-1 in endothelial cells.

Cell Hypoxia↗
PubMed1996

PRB1, PRB2, and PRB4 coded polymorphisms among human salivary concanavalin-A binding, II-1, and Po proline-rich proteins.

Six closely linked PRP (proline-rich protein) genes code for many salivary PRPs that show frequent length and null variants. From determined protein sequences and DNA sequence analysis of variant alleles, we here report the coding and molecular basis for Con (concanavalin A-binding) and Po (parotid "o") protein polymorphisms. The Con1 glycoprotein is encoded in exon 3 of a PRB2 allele (PRB2L CON1+) with a potential N-linked glycosylation site. Because of a probable gene conversion encompassing > or = 684 bp of DNA, the "PRB2-like" Con2 glycoprotein is encoded in exon 3 of a PRB1 allele (PRB1M CON2+) with a potential glycosylation site. The PmF protein is also encoded in the PRB1M CON2+ allele, thus explaining the previously reported association between Con2 and PmF proteins. A PRB2L CON1 allele contains a single nt missense change [TCT(Ser)-->CCT (Pro)] that abolishes the potential N-linked glycosylation site (NKS-->NKP) in the Con1 protein, and this explains the Con- type. The Po protein and a glycoprotein (II-1) are encoded in the PRB4 gene, and both proteins are absent in the presence of a mutation in the PRB4M PO- allele that contains a single nt change (G--C) at the +1 invariant position of the intron 3 5'donor splice site. The genetically determined absence of the II-1 glycoprotein leads to altered in vitro binding of Streptococcus sanguis 10556 to salivary proteins, which suggests a biological consequence for null mutations of the PRB4 gene.

Alleles↗