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At least 415 records · Page 23Linked to original sources
PubMed2006

Absence of pathogenic calcium sensing receptor mutations in sporadic idiopathic hypoparathyroidism.

BACKGROUND: Sporadic idiopathic hypoparathyroidism (SIH) is the most common cause of hypoparathyroidism. While calcium sensing receptor (CaSR) autoantibodies are observed in 49% of cases, aetiopathogenetic mechanisms in others are under investigation. Mutations in the PTH gene including its 3' untranslated region, autoimmune regulator gene and lead CTLA-4 gene single nucleotide polymorphism (SNPs) are not associated with the disease. There are reports of de novo activating mutations of the CaSR gene in a few patients with SIH. OBJECTIVE: To assess the frequency of CaSR mutations in patients with SIH. SUBJECTS AND METHODS: DNA sequencing of all six translating exons and nine of 12 intron/exon boundaries of the CaSR gene was performed by Sangers dideoxy chain termination method using an automated sequencer in 39 patients with SIH. Spot urinary calcium/creatinine ratio in the fasting state and ultrasonography of the abdomen was performed to assess hypercalciuria and nephrolithiasis. The PCR-RFLP analysis was performed using Hin1II restriction endonuclease in 32 additional patients with SIH and 90 healthy controls to further assess the prevalence of a novel missense SNP observed in the DNA sequencing. RESULTS: Nucleotide sequence analysis revealed the presence of a wild type CaSR gene in all subjects, except in one patient who showed a missense mutation (Val621Met) due to substitution of base G-->A in the heterozygous state at position 79877 in exon 7 (codon 621) coding for the first transmembrane loop of the CaSR. The V621M polymorphism was confirmed by PCR-RFLP and was due to a maternal allele. However, the mother and brother of this patient with the same SNP were asymptomatic and had normal serum chemistry indicating the functionally inert nature of the polymorphism. None of the additional 32 patients with SIH and 90 controls showed V621M SNP. The urinary calcium/creatinine ratio and ultrasonography were normal in all patients with SIH. CONCLUSION: De novo activating mutation of the CaSR gene typical of familial hypoparathyroidism is not common among patients with SIH in India.

Adult↗
PubMed2005

The human TBX5 gene mutation database.

Germline mutations of the TBX5 gene were identified as the primary cause in up to 70% of patients with Holt-Oram syndrome (HOS), an autosomal dominant disorder characterized by malformations of the upper limbs and cardiac defects. Furthermore, somatic mutations of the TBX5 gene have been described in diseased heart tissues of patients with congenital heart defects of different cause. The relationship between genotype and phenotype remains unclear and the underlying mechanism of the pathogenic effect is not solved. In this report, we introduce the 'TBX5 Gene Mutation Database,' an online locus specific database containing germline and somatic mutations of the TBX5 gene. The permanently updated data collection includes all reported mutations beginning with the first description of the gene in 1997. With our database we complement the existing resources by: 1) giving a complete review of the so far reported mutation spectrum in TBX5 considering the clinical relevance; 2) linkage of the mutational data to the corresponding gene location and PubMed-Abstracts; and 3) additional links to other related resources like SNP database, sequences and literature references. The usage of our database will help to quickly find informations about genetic variations within the TBX5 gene. Here we describe the database structure, content, and potential applications (http://www.uni-leipzig.de/~genetik/TBX5).

Databases, Genetic↗
PubMed2005

Genomic scans for selective sweeps using SNP data.

Detecting selective sweeps from genomic SNP data is complicated by the intricate ascertainment schemes used to discover SNPs, and by the confounding influence of the underlying complex demographics and varying mutation and recombination rates. Current methods for detecting selective sweeps have little or no robustness to the demographic assumptions and varying recombination rates, and provide no method for correcting for ascertainment biases. Here, we present several new tests aimed at detecting selective sweeps from genomic SNP data. Using extensive simulations, we show that a new parametric test, based on composite likelihood, has a high power to detect selective sweeps and is surprisingly robust to assumptions regarding recombination rates and demography (i.e., has low Type I error). Our new test also provides estimates of the location of the selective sweep(s) and the magnitude of the selection coefficient. To illustrate the method, we apply our approach to data from the Seattle SNP project and to Chromosome 2 data from the HapMap project. In Chromosome 2, the most extreme signal is found in the lactase gene, which previously has been shown to be undergoing positive selection. Evidence for selective sweeps is also found in many other regions, including genes known to be associated with disease risk such as DPP10 and COL4A3.

Black or African American↗
PubMed2002

Expression of myostatin is not altered in lines of poultry exhibiting myofiber hyper- and hypoplasia.

Decades of selective breeding have yielded lines of poultry with substantial myofiber hyperplasia, vet little is known about what genes have been altered during the course of selection. Myostatin is a strong negative regulator of muscle mass in mice and cattle and could have been one of many genetic factors contributing to increased myofiber deposition in growth-selected lines of poultry. To test this hypothesis, the sequence and expression patterns of myostatin were analyzed in growth-selected lines of chickens and quail. The sequence of broiler myostatin cDNA, amplified via reverse transcription (RT)-PCR from embryonic muscle RNA, contained no missense mutations in the coding sequence when compared to that of White Leghorn layers, although two silent single nucleotide polymorphisms (SNP) were found. Northern analysis of myostatin transcripts from embryonic pectoralis and quadriceps showed no significant differences in expression levels between broiler and layer muscle RNA. However, levels of myostatin transcripts were greatly reduced in muscles of posthatch chicks compared to embryonic muscle. Myostatin protein was also present in broiler and layer embryonic muscle at similar levels. No significant polymorphisms or differences in RNA expression levels were found in embryonic muscles of divergently selected lines of Japanese quail. These results indicate that intense artificial selection in these growth-selected lines of poultry has neither silenced the expression of myostatin nor created null alleles via mutation in the lines analyzed.

Animal Husbandry↗
PubMed2002

[Identification of new mutant sites and 894C deletion variant genotyping of HIV-1 coreceptor CCR5 in indigenous Chinese populations].

OBJECTIVE: To investigate the new single nucleotide polymorphism (SNP) sites of HIV-1 coreceptor CCR5 gene and conduct genotyping of CCR5-894C deletion allele in Chinese populations. METHODS: The full length fragment of CCR5 gene coding region was amplified by PCR amplification and sequenced in 45 healthy subjects from Han ethnic group. The sequencing data was analyzed by using DNAstar software for identification of new SNP sites. Furthermore, the genotyping of CCR5-894C deletion variant was performed by PCR-RFLP assay in 627 indigenous Chinese individuals including HIV-1 carriers, HIV-1 high risk population of STDs or IDUs as well as normal contrast. RESULTS: Totally six SNPs and one cytosine base deletion at the 894 nucleotide of CCR5 gene coding region were found in forty five Chinese Han subjects. Four SNPs, i.e. 184A-->G, 503G-->T, 668G-->A, 999G-->T, cause alteration of corresponding amino acids in CCR5 protein and two SNPs are nonsense mutations. The 894C deletion mutation results in a frame shift mutation of CCR5 gene. Among the six SNPs identified, the three sites 184A-->G, 503G-->T, 999G-->T were firstly reported only in Chinese people. The allelic frequencies of mutant 184G, 503T and 999T alleles were 1.1%, 21.1% and 10.0% in Han healthy subjects, respectively. PCR-RFLP assay showed the frequencies of CCR5-894C deletion alleles are 1.11%, 0.53% and 0% for Chinese Han, Tibetan and Mongolian healthy individuals, respectively. There was not significant different of the frequencies of CCR5-894C deletion allele among HIV-1 high risk populations, HIV-1 carries and healthy subjects. CONCLUSION: The subjects from Chinese Han group has its own distinctive SNP sites in the HIV-1 coreceptor CCR5 gene, three new SNPs (184A-->G, 503G-->T, 999G-->T) were firstly identified. Taking together, the significance and implication of these distinctive SNP sites and the 894C deletion mutation in the pathogenesis of HIV/AIDS disease need to be further studied.

Amino Acid Sequence↗
PubMed2005

Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism.

OBJECTIVE: To determine the frequency of mutations of the gonadotropin-releasing hormone receptor (GnRHR) and of the G protein-coupled receptor 54 (GPR54) genes in normosmic idiopathic hypogonadotropic hypogonadism (IHH). METHODS: In a retrospective study we analyzed the GnRHR and the GPR54 genes of 45 IHH patients and 50 controls. Genomic DNA was amplified by PCR to obtain partially overlapping amplicons encompassing the exon-intron boundaries of the GnRHR and GPR54 genes and analyzed by single-stranded conformation polymorphism gel electrophoresis and/or DNA sequencing. RESULTS: One heterozygous R262Q mutation of the GnRHR gene was identified in one patient with familial IHH. The silent single-nucleotide polymorphism (SNP) 453C > T occurred at the same frequency in patients and controls. One patient with sporadic IHH and consanguineous parents showed a novel homozygous sequence variation of the GPR54 gene (1001_1002insC) resulting in an open reading frame shift and elongation of 43 amino acids with an increased number of proline residues in the intracellular receptor domain. This patient had delayed puberty, low testosterone (3.4 nmol/l), and low-normal LH and FSH levels responsive to GnRH. Pulsatile GnRH administration normalized testosterone levels and induced spermatogenesis sufficiently to induce a pregnancy with assisted reproduction. Two common SNPs in exon 1 and exon 5 of the GPR54 gene showed similar frequency distribution and hormonal profiles in IHH and controls. CONCLUSIONS: Mutations of the GnRHR and of the GPR54 gene are rare in IHH and should be investigated especially in cases with autosomal recessive transmission. Common SNPs of the GnRHR and GPR54 genes do not play any role in IHH.

Adolescent↗
PubMed2006

A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia.

Phosphodiesterases (PDEs) regulate cyclic nucleotide levels. Increased cyclic AMP (cAMP) signaling has been associated with PRKAR1A or GNAS mutations and leads to adrenocortical tumors and Cushing syndrome. We investigated the genetic source of Cushing syndrome in individuals with adrenocortical hyperplasia that was not caused by known defects. We performed genome-wide SNP genotyping, including the adrenocortical tumor DNA. The region with the highest probability to harbor a susceptibility gene by loss of heterozygosity (LOH) and other analyses was 2q31-2q35. We identified mutations disrupting the expression of the PDE11A isoform-4 gene (PDE11A) in three kindreds. Tumor tissues showed 2q31-2q35 LOH, decreased protein expression and high cyclic nucleotide levels and cAMP-responsive element binding protein (CREB) phosphorylation. PDE11A codes for a dual-specificity PDE that is expressed in adrenal cortex and is partially inhibited by tadalafil and other PDE inhibitors; its germline inactivation is associated with adrenocortical hyperplasia, suggesting another means by which dysregulation of cAMP signaling causes endocrine tumors.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2005

Potentiometric Detection of Single Nucleotide Polymorphism by Using a Genetic Field-effect transistor.

Potentiometric measurement of allele-specific oligonucleotide hybridization based on the principle of detection of charge-density change at the surface of a gate insulator by using of a genetic field-effect transistor has been demonstrated. Since DNA molecules are negatively charged in aqueous solution, a hybridization event at the gate surface leads to a charge-density change in the channel of the FET and can be directly transduced into an electrical signal without any labeling of target DNA molecules. One of the unique features of our method is to utilize DNA binders such as intercalators as charged species for double-stranded DNA after hybridization, since these are ionized and carry positive charges in aqueous solution. Single-base mismatch of the target DNA could be successfully detected both with the wild-type and with the mutant genetic FETs by controlling the hybridization temperatures and introducing Hoechst 33258 as DNA binder. The genetic FET platform is suitable as a simple, accurate, and inexpensive system for SNP typing in clinical diagnostics.

DNA↗
PubMed2001

Recent developments in high-throughput mutation screening.

Screening of large sample materials for the presence of known or unknown mutations is a key element in pharmacogenomics. Although automated DNA sequencing has developed rapidly during the last decade, the technology is not well suited for projects involving analysis of hundreds of thousands of mutations. Consequently, a number of methods for high-throughput mutation screening have been developed. DNA microarrays and high-density oligonucleotide chips have proven to be well suited for parallel hybridisation-based analysis of hundreds or thousands of known mutations. Methods based on detection using matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) have been developed. MALDI-TOF MS detection is limited to analysis of small DNA fragments but has a large potential for high-throughput single nucleotide polymorphism (SNP) analysis, due to a very fast analysis time and possibilities for automation. Currently, the best suited methods for high-throughput screening for unknown mutations are probably methods like single strand conformation polymorphism (SSCP) analysis or conformation sensitive gel electrophoresis (CSGE), combined with capillary array electrophoresis or denaturing high-performance liquid chromatography. This is due to a relatively short analysis time, potential for automation and a high sensitivity. The recent development of capillary array electrophoresis chips suggests that the analysis time for some of these methods may be reduced by one order of magnitude in the near future.

Chromatography, High Pressure Liquid↗
PubMed2002

Identification of single-nucleotide polymorphisms in the human LPIN1 gene.

Because mutations in the murine analog of human LPIN1 cause lipodystrophy in mice, LPIN1 is a candidate gene for human lipodystrophy syndromes. To identify possible disease mutations and/or common single-nucleotide polymorphisms (SNPs), we developed primer pairs to amplify the 21 exons of LPIN1. We used these primer pairs to sequence LPIN1 in lipodystrophy patients who had no mutations in known lipodystrophy genes, and also in normal control subjects. We found no rare LPIN1 coding sequence variants that were exclusive to patients with lipodystrophy. However, we found four silent SNPs, namely, +17C>T in exon 3, 935C>T in exon 5, and 1040G>A and 1079G>C in exon 6, and one nonsynonymous SNP, namely, 2211C>T (P616S) in exon 15. The findings suggest that LPIN1mutations are not commonly seen in patients with lipodystrophy who had no mutations in known disease genes. However, the identification of amplification primers and SNPs provides tools to further investigate LPIN1for association with other phenotypes.

Animals↗
PubMed2006

Porcine APP cDNAs: molecular cloning and characterization, expression analysis, chromosomal localization and SNP analysis.

The human amyloid precursor protein (APP) is the precursor of Abeta, a peptide with the potential to create amyloid plaques in neurons. Mutations in the human APP gene are associated with the familial form of Alzheimer's disease. In addition, differential expression of three alternative pre-mRNA APP splicing variants of 695, 751, and 770 amino acids is linked to the pathogenesis. In this study, two novel transcript variants of porcine APP have been identified, producing isoforms of 695 and 751 amino acids, respectively. These are highly homologous to APP orthologues from other vertebrate species. Expression analyses revealed that the gene is expressed in all 30 examined porcine tissues and in a selected subset of these, differential representation of the three major APP transcript variants was observed. The APP isoform of 770 amino acids clearly predominates in non-neuronal tissues while in porcine cerebellum, the APP isoforms of 695 and 770 amino acids are expressed at equivalent levels. Employing a somatic cell hybrid panel, the APP gene was mapped to porcine chromosome 13 in either the 13q41 or 13q46-q49 region. A large pig population was screened for single nucleotide polymorphisms (SNPs) in APP exon 17 and flanking intron sequences. No missense mutations were detected; however, the allele frequencies of two silent mutations and two intron polymorphisms varied significantly among breeds.

Amino Acid Sequence↗
PubMed2006

Mutation of the follicle-stimulating hormone receptor gene 5'-untranslated region associated with female hypertension.

Inactivating mutations in the follicle-stimulating hormone receptor (FSHR) gene have been reported to cause hereditary hypergonadotropic ovarian failure. It has been found recently that the FSHR knockout mouse exhibits hypertension. The aim of the present study was to investigate the association between polymorphisms in the human FSHR gene and essential hypertension (EH) by using single nucleotide polymorphisms (SNPs). We selected 5 SNPs in the gene (rs1394205, rs2055571, rs11692782, rs1007541, and rs2268361) and performed 2 genetic case-control studies in different populations. A confirmative case-control study was performed using 1035 EH patients and 1058 age-matched controls. Transcriptional activities were measured with a luciferase assay system. The first case-control study found that the A allele of rs1394205 was significantly higher in EH females (P=0.010). In addition, in the confirmative case-control study, there was a significant difference for this SNP between female normotensive subjects (44.5%) and EH patients (50.7%) (P=0.043). Multiple logistic regression analysis in female subjects also revealed a significant association of subjects with the A allele of rs1394205 with EH (P=0.033), with the odds ratio calculated as 1.68 (95% CI: 1.04 to 2.73). Transcriptional activity of the A allele was 56+/-8% (mean+/-SD) of that observed for the G-type allele (P=0.001). Serum estradiol levels were significantly lower in patients with the A/A genotype than in patients without the A/A genotype (P=0.004). The SNP in the 5'-untranslated region of the FSHR gene affects levels of transcriptional activity and is a susceptibility mutation of EH in women.

5' Untranslated Regions↗
PubMed2002

Novel polymorphisms in the somatostatin receptor 5 (SSTR5) gene associated with bipolar affective disorder.

The somatostatin receptor 5 (SSTR5) gene is a candidate gene for bipolar affective disorder (BPAD) as well as for other neuropsychiatric disorders. The gene is positioned on chromosome 16p13.3, a region that has been implicated by a few linkage studies to potentially harbor a disease susceptibility gene for BPAD. Recent evidence shows that the dopamine D2 receptor (DRD2) and SSTR5 interact physically to form heterodimers with enhanced functional activity. Brain D2 dopamine receptors are one of the major targets of neuroleptic treatments in psychiatric disorders. In this study we systematically screened the promoter and coding region of the SSTR5 gene for genetic variation that could contribute to the development of neuropsychiatric disorders. Eleven novel single nucleotide polymorphisms (SNPs) were identified including four missense SNPs, Leu48Met, Ala52Val, Pro109Ser and Pro335Leu. We carried out an association study of BPAD using 80 Danish cases and 144 control subjects, and replication analysis using 55 British cases and 88 control subjects. For the Danish population, association was suggested between silent SNP G573A and BPAD (P = 0.008). For the British population we found association to BPAD with missense mutation Leu48Met (P = 0.003) and missense mutation Pro335Leu (P = 0.004). The statistical significance of the association was, however, greatly reduced after correcting for multiple testing. When combining genotypes from Leu48Met and Pro335Leu into haplotypes, association to BPAD was found in the British population (P = 0.0007). This haplotype association was not replicated in the Danish population. Our results may indicate that the SSTR5 gene is involved in the etiology of BPAD or may exist in linkage disequilibrium with a susceptibility gene close to SSTR5. However, given the marginal statistical significance and the potential for false-positive results in association studies with candidate genes, further studies are needed to clarify this hypothesis.

Bipolar Disorder↗
PubMed2006

Probing genomic diversity and evolution of Escherichia coli O157 by single nucleotide polymorphisms.

Infections by Shiga toxin-producing Escherichia coli O157:H7 (STEC O157) are the predominant cause of bloody diarrhea and hemolytic uremic syndrome in the United States. In silico comparison of the two complete STEC O157 genomes (Sakai and EDL933) revealed a strikingly high level of sequence identity in orthologous protein-coding genes, limiting the use of nucleotide sequences to study the evolution and epidemiology of this bacterial pathogen. To systematically examine single nucleotide polymorphisms (SNPs) at a genome scale, we designed comparative genome sequencing microarrays and analyzed 1199 chromosomal genes (a total of 1,167,948 bp) and 92,721 bp of the large virulence plasmid (pO157) of eleven outbreak-associated STEC O157 strains. We discovered 906 SNPs in 523 chromosomal genes and observed a high level of DNA polymorphisms among the pO157 plasmids. Based on a uniform rate of synonymous substitution for Escherichia coli and Salmonella enterica (4.7x10(-9) per site per year), we estimate that the most recent common ancestor of the contemporary beta-glucuronidase-negative, non-sorbitolfermenting STEC O157 strains existed ca. 40 thousand years ago. The phylogeny of the STEC O157 strains based on the informative synonymous SNPs was compared to the maximum parsimony trees inferred from pulsed-field gel electrophoresis and multilocus variable numbers of tandem repeats analysis. The topological discrepancies indicate that, in contrast to the synonymous mutations, parts of STEC O157 genomes have evolved through different mechanisms with highly variable divergence rates. The SNP loci reported here will provide useful genetic markers for developing high-throughput methods for fine-resolution genotyping of STEC O157. Functional characterization of nucleotide polymorphisms should shed new insights on the evolution, epidemiology, and pathogenesis of STEC O157 and related pathogens.

Chromosome Mapping↗
PubMed2006

Functional validation of the genetic polymorphisms of human ATP-binding cassette (ABC) transporter ABCG2: identification of alleles that are defective in porphyrin transport.

The ATP-binding cassette (ABC) transporter ABCG2 has been implicated to play a significant role in the response of patients to medication and/or the risk of diseases. To clarify the possible physiological or pathological relevance of ABCG2 polymorphisms, we have functionally validated single nucleotide polymorphisms (SNP) of ABCG2. In the present study, based on the currently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in insect cells. Because porphyrins are considered to be endogenous substrates for ABCG2, we have investigated the porphyrin transport activity of those variant forms in vitro. We herein provide evidence that the variants Q126stop, F208S, S248P, E334stop, and S441N are defective in porphyrin transport, whereas F489L exhibited impaired transport, approximately 10% of the activity observed for the wild type. Furthermore, Flp-In-293 cells expressing those variants were photosensitive. Thus, among those genetic polymorphisms of ABCG2, at least the hitherto validated alleles of Q126stop, S441N, and F489L are suggested to be of clinical importance related to the potential risk of porphyria.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2005

Superb nucleotide discrimination by a novel on/off switch for DNA polymerization and its applications.

With the use of polymerases having 3' to 5' exonuclease activity and 3' phosphorothioate-modified allele-specific primers, we recently devised a SNP-operated on/off switch controlling DNA polymerization. One advantage of this novel on/off switch is its adaptability to arrayed primer extension. To further expand its application in genetic analysis, this new on/off switch was evaluated in discrimination of the match/mismatch status of single nucleotides upstream from the primer 3' terminal. A set of seven amplicons was developed with the templates differing from each other by a single nucleotide. Using this set of amplicons, the new on/off switch was shown to be able to efficiently discriminate single nucleotide polymorphisms from the primer 3' terminus to the -6 position from the primer 3' terminus. These data, illustrating the broad single nucleotide discrimination ability of this novel on/off switch, explain why the SNP-operated on/off switch is powerful in SNP analysis, and also indicate useful applications to genetic analysis additional to SNP assay. First, these data broaden the application of the novel on/off switch in the analysis of mutations other than SNPs. Second, it raises a nucleotide-walking algorithm suitable for de novo array-based sequencing analysis.

DNA Mutational Analysis↗
PubMed2004

Evaluation of haplotypes associated with copper toxicosis in Bedlington Terriers in Australia.

OBJECTIVE: To evaluate the haplotype distribution associated with the copper toxicosis gene and the segregation of the mutated allele in a Bedlington Terrier population in Australia. ANIMALS: 131 Bedlington Terriers. PROCEDURE: Samples of DNA and RNA were obtained from each dog. Genetic status of each dog was evaluated by use of the DNA markers C04107; single nucleotide polymorphism (SNP), which was adjacent to exon 2 of Murr1; and a deletion marker for exon 2. A subgroup of the study population was evaluated by use of biochemical and histologic techniques to elucidate the correlation between genotype and phenotype. RESULTS: We identified a recombination between the C04107 marker and Murr1 and a variation in a nucleotide in the splice site of exon 2 in our Bedlington Terrier cohort. Furthermore, we identified a novel haplotype associated with copper toxicosis in this cohort. CONCLUSIONS AND CLINICAL RELEVANCE: Our findings indicate that the deletion of exon 2 was not the sole cause of copper toxicosis, although only exon 2 deletion of Murr1 has been responsible for copper toxicosis in Bedlington Terriers. Although we failed to find a novel mutation in our cohort, we identified an affected dog family with an intact exon 2. Furthermore, we found that an SNP in the 5' splicing site of exon 2 may or may not be associated with a novel mutation of the Murr1 gene or other genes. Loss of linkage between the C04107 marker and the Murr1 gene was also identified in a certain family of dogs.

Animals↗
PubMed2006

Allele frequencies of three factor VIII gene polymorphisms in Iranian populations and their application in hemophilia A carrier detection.

Hemophilia A is an X-linked recessive bleeding disorder caused by a quantitative or qualitative deficiency of blood coagulation factor VIII (FVIII). ARMS (amplification refractory mutation system) primers were designed to determine allele frequencies of three FVIII gene linked markers, IVS7 nt 27 G/A SNP, BclI/intron 18, and HindIII/intron 19 among 85 normal Iranian women from unrelated families. Then same method was applied to perform carrier detection for hemophilia A families. The allele frequencies of IVS7 nt 27 "G"/"A" allele, BclI "T"/"A" allele, and HindIII "C"/"T" allele among normal women were 0.88/0.12, 0.52/0.48, and 0.48/0.52, respectively. The three polymorphisms were found to be in strong linkage disequilibrium, which decreased the overall heterozygosity to 51%. Twenty-one women from 15 unrelated hemophilia A families were referred to us for hemophilia A carrier detection. Taking advantage of these three biallelic polymorphisms in conjunction with multiallelic St14 VNTR (locus DXS52), IVS13 (CA)n STR, and IVS22 (CA)n STR, carrier status was determined in 16 women (16/21 or 76% of the at-risk women) from 11 families (11/15 or 73% of the families). The used ARMS methods are rapid and can easily be applied in conjunction with other FVIII gene linked polymorphisms for indirect mutation detection of hemophilia A where they are informative.

Factor VIII↗