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At least 505 records · Page 28Linked to original sources
PubMed2006

Identification of germline MLH1 alterations in familial prostate cancer.

Several linkage and loss of heterozygosity (LOH) analyses suggest that the region 3p21-p26, which is a chromosomal location of MLH1, could harbour a susceptibility gene for prostate cancer (PRCA). Furthermore, in a recent candidate single nucleotide polymorphism (SNP) analysis the I219V variation of the MLH1 gene was associated with PRCA. Microsatellite instability (MSI) and germ-line MLH1 mutations were originally demonstrated in hereditary non-polyposis colorectal cancer (HNPCC) but MSI and loss of MLH1 function have also been detected in PRCA. To assess the contribution of MLH1 germline mutations to the development of PRCA in Finland different approaches were used. First, the samples from 11 PRCA-colon cancer patients were screened for MLH1, MSH2 and MSH6 protein expression by immunohistochemistry (IHC). IHC revealed one patient with a putative MLH1 aberration and sequencing of this sample revealed five sequence variants including two missense variants P434L and I219V. Second, the samples from Finnish hereditary prostate cancer (HPC) families were used for the screening of MLH1 mutations which produced twelve MLH1 sequence variants including two missense mutations, I219V, as in the PRCA-colon cancer patient, and V647M. P434L and V647 were both novel, rare variants. Carrier frequencies of the I219V mutation were compared between hereditary prostate cancer (HPC) patients, unselected PRCA cases, patients with benign prostate hyperplasia and controls, but no differences between the sample groups were found. P434L was not present in this study population and V647M was a very rare variant found only in one HPC family. According to the present results, MLH1 does not have a major role in PRCA causation in Finland.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Genetic variations in IL6 associate with intervertebral disc disease characterized by sciatica.

Intervertebral disc disease (IDD) characterized by sciatica is a common disorder affecting about 5% of individuals. Environmental factors can predispose to this disease, but IDD has a strong genetic background. Recent evidence suggests that inflammation is one of the key factors in the etiology of IDD. Here, a possible role of the inflammatory mediator genes was studied in 155 patients with IDD-related sciatica and 179 controls. Forty-eight patients were analyzed for mutations in the IL1A, IL1B, IL6 and TNFA genes, and 16 polymorphisms in 10 candidate cytokine genes (IL1A, IL1B, IL1RN, TNFA, IL2, IL4, IL4R, IL6, IL10, IFNG) were genotyped from all subjects. No disease-causing mutations were identified in IL1A, IL1B, IL6 or TNFA. Allele frequencies were, however, significantly different between the two groups for IL6 SNP, T15A in exon 5 (P=0.007). Furthermore, the genotypes AA and AT of the exon 5 SNP were more common in the patients (P=0.011; OR=4.4, 95% CI=1.2-15.7; AR=7.5%, 1.6-13.1%). Haplotypes were then generated for four IL6 SNPs, G-597A, G-572C, G-174C, and T15A in exon 5. Haplotype GGGA was more common in the patients (P=0.011; OR=4.8, 95% CI=1.6-14.5). To evaluate attributable risk, haplotype pairs were assigned for the individuals. The presence of GGGA/GGGA or GGGA/other genotypes had an OR of 5.4 (95% CI=1.5-19.2). Association of GGGA with disease was highly significant (P=0.0033), and the associated AR was 6.8% (1.9-11.5%). These findings support the role of IL-6 genetic variations in discogenic pain.

Adult↗
PubMed2006

Disruption of POF1B binding to nonmuscle actin filaments is associated with premature ovarian failure.

Premature ovarian failure (POF) is characterized by elevated gonadotropins and amenorrhea in women aged <40 years. In a Lebanese family with five sisters who received the diagnosis of POF, we established linkage to the long arm of the X chromosome (between Xq21.1 and Xq21.3.3), using whole-genome SNP typing and homozygosity-by-descent mapping. By sequencing one candidate gene within that region, POF1B, we identified a point mutation localized in exon 10. This substitution of a nucleotide (G-->A), at position 1123, results in an arginine-->glutamine mutation of the protein sequence at position 329 (mutation R329Q). All the affected family members were homozygous for the mutation, whereas the unaffected members were heterozygous. Because POF1B shares high homology with the tail portion of the human myosin, we assessed the ability of both wild-type and mutant POF1B proteins to bind nonmuscle actin filaments in vitro. We found that the capacity of the mutant protein to bind nonmuscle actin filaments was diminished fourfold compared with the wild type, suggesting a function of POF1B in germ-cell division. Our study suggests that a homozygous point mutation in POF1B influences the pathogenesis of POF by altering POF1B binding to nonmuscle actin filaments.

Actins↗
PubMed2005

Bioinformatics approaches and resources for single nucleotide polymorphism functional analysis.

Since the initial sequencing of the human genome, many projects are underway to understand the effects of genetic variation between individuals. Predicting and understanding the downstream effects of genetic variation using computational methods are becoming increasingly important for single nucleotide polymorphism (SNP) selection in genetics studies and understanding the molecular basis of disease. According to the NIH, there are now more than four million validated SNPs in the human genome. The volume of known genetic variations lends itself well to an informatics approach. Bioinformaticians have become very good at functional inference methods derived from functional and structural genomics. This review will present a broad overview of the tools and resources available to collect and understand functional variation from the perspective of structure, expression, evolution and phenotype. Additionally, public resources available for SNP identification and characterisation are summarised.

Algorithms↗
PubMed2005

Sequence variation in G-protein-coupled receptors: analysis of single nucleotide polymorphisms.

We assessed the disease-causing potential of single nucleotide polymorphisms (SNPs) based on a simple set of sequence-based features. We focused on SNPs from the dbSNP database in G-protein-coupled receptors (GPCRs), a large class of important transmembrane (TM) proteins. Apart from the location of the SNP in the protein, we evaluated the predictive power of three major classes of features to differentiate between disease-causing mutations and neutral changes: (i) properties derived from amino-acid scales, such as volume and hydrophobicity; (ii) position-specific phylogenetic features reflecting evolutionary conservation, such as normalized site entropy, residue frequency and SIFT score; and (iii) substitution-matrix scores, such as those derived from the BLOSUM62, GRANTHAM and PHAT matrices. We validated our approach using a control dataset consisting of known disease-causing mutations and neutral variations. Logistic regression analyses indicated that position-specific phylogenetic features that describe the conservation of an amino acid at a specific site are the best discriminators of disease mutations versus neutral variations, and integration of all our features improves discrimination power. Overall, we identify 115 SNPs in GPCRs from dbSNP that are likely to be associated with disease and thus are good candidates for genotyping in association studies.

Amino Acid Substitution↗
PubMed2003

Haplotype analysis of the human renin gene and essential hypertension.

The human renin gene is an attractive candidate for involvement in the underlying cause of essential hypertension (EH). Despite extensive examination, the relation between the renin gene and hypertension remains unclear. The aims of the present study were to discover new genetic markers of EH and to investigate the relations between polymorphisms of the renin gene and EH in the Japanese. Using the polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) method, we isolated 3 novel variants of the renin gene; a single nucleotide polymorphism (SNP) in intron 4 (T+17int4G), a variable number of tandem repeats (VNTR) polymorphism in intron 7, and a missense mutation in exon 9 (G1051A). We performed an association study with these polymorphisms in 212 patients with EH and 209 age-matched normotensive (NT) subjects. The frequency of genotypes VNTR and T+17int4G did not differ significantly between the 2 groups, whereas the overall distribution of G1051A was significantly different between EH and NT. Haplotype analysis revealed that the overall distribution of haplotypes differed significantly between the EH and NT groups. PRA levels in patients with EH with the G/G genotype were significantly higher than in subjects with EH with G/A and A/A genotypes. These data suggest that the missense mutation in exon 9 may affect the enzymatic function of renin and consequently may be involved in the etiology of hypertension.

Adult↗
PubMed2006

Tumor necrosis factor alpha but not interleukin 1 beta mediates neuroprotection in response to acute nitric oxide excitotoxicity.

Neurodegenerative processes in the brain are accompanied by activation of innate immunity, which involves the release of proinflammatory cytokines by microglia and infiltrating macrophages. The beneficial or detrimental roles of these cytokines, including interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha), remain to be clarified. These cytokines have numerous overlapping activities that make it difficult to interpret data generated by mice that have a mutation in the gene encoding either TNF-alpha or IL-1beta. To remediate the problem, we generated a mouse that bears a mutation in both genes and exposed them to an acute neurotoxic insult. Intracerebral infusion with the nitric oxide donor sodium nitroprusside (SNP) caused neurodegeneration and demyelination that were markedly increased in the brain of TNF-alpha- and IL-1beta/TNF-alpha-deficient mice compared with IL-1beta-deficient and wild-type mice. Surprisingly, TNF and double mutants exhibited an early (6 h after SNP injections) blunted microglial activation followed by an exaggerated response later on (4 d later). No differences were found in the brain of the IL-1beta knock-out and wild-type groups. This suggests a crucial role for TNF-alpha in mediating microglial reactivity to acute injury. An immediate response clearly helps eliminate cell debris, restrict subsequent damages, and restore homeostasis. These findings may have direct implications for the use anti-inflammatory drugs in acute neurodegenerative and demyelinating disorders.

Animals↗
PubMed2006

His239Arg SNP of HRAD9 is associated with lung adenocarcinoma.

BACKGROUND: It was previously reported that a functional human (h) Rad9 protein accumulated in the nuclei of non-small cell lung carcinoma (NSCLC) cells. Those experiments, however, did not examine whether the hRad9 gene was mutated in those cells. The sequence of the HRAD9 gene in NSCLC cells was investigated. METHODS: The sequence of the HRAD9 was examined in tumor and peripheral normal lung tissues obtained from 50 lung adenocarcinoma patients during surgery. The expression of its mRNA using reverse transcription polymerase chain reaction (RT-PCR) was also examined. RESULTS: No sequence alterations were detected in the HRAD9 gene, which was found to be normally transcribed in surgically resected lung carcinoma cells. However, in eight (16.0%) cases a single nucleotide polymorphism (SNP) was observed at the second position of codon 239 (His/Arg heterozygous variant) of the gene. This frequency was significantly higher than that found in the normal population. CONCLUSIONS: Whereas the capacity to produce a functional hRad9 protein was intact in lung adenocarcinoma cells, a nonsynonymous SNP of HRAD9 was detected that might be associated with the development of lung adenocarcinoma.

Adenocarcinoma↗
PubMed2006

East Asian mtDNA haplogroup determination in Koreans: haplogroup-level coding region SNP analysis and subhaplogroup-level control region sequence analysis.

The present study analyzed 21 coding region SNP markers and one deletion motif for the determination of East Asian mitochondrial DNA (mtDNA) haplogroups by designing three multiplex systems which apply single base extension methods. Using two multiplex systems, all 593 Korean mtDNAs were allocated into 15 haplogroups: M, D, D4, D5, G, M7, M8, M9, M10, M11, R, R9, B, A, and N9. As the D4 haplotypes occurred most frequently in Koreans, the third multiplex system was used to further define D4 subhaplogroups: D4a, D4b, D4e, D4g, D4h, and D4j. This method allowed the complementation of coding region information with control region mutation motifs and the resultant findings also suggest reliable control region mutation motifs for the assignment of East Asian mtDNA haplogroups. These three multiplex systems produce good results in degraded samples as they contain small PCR products (101-154 bp) for single base extension reactions. SNP scoring was performed in 101 old skeletal remains using these three systems to prove their utility in degraded samples. The sequence analysis of mtDNA control region with high incidence of haplogroup-specific mutations and the selective scoring of highly informative coding region SNPs using the three multiplex systems are useful tools for most applications involving East Asian mtDNA haplogroup determination and haplogroup-directed stringent quality control.

Asian People↗
PubMed2002

Glucocorticoid receptor variants: clinical implications.

Following exposure to stress, cortisol is secreted from the adrenal cortex under the control of the hypothalamic-pituitary-adrenal axis (HPA-axis). Central in the regulation of the HPA-axis is a two tied corticosteroid-receptor system, comprised of high and low affinity receptors, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), respectively. In addition, these corticosteroid receptors mediate the effects of cortisol during stress on both central and peripheral targets. Cortisol modulates gene-expression of corticosteroid-responsive genes, with the effect lasting from hours to days. Mutations in the GR-gene are being associated with corticosteroid resistance and haematological malignancies, although these mutations are relatively rare and probably not a common cause of these diseases. However, several GR-gene variants and single nucleotide polymorphisms (SNP) in the GR-gene have been identified which are relatively common in the human population. The GRbeta-variant, for example, has been proposed to influence corticosteroid-sensitivity and most evidence has been derived from the immune system and in particular asthma. With respect to polymorphisms, a BclI restriction fragment polymorphism and a Asp363Ser have been described, which not only influence the regulation of the HPA-axis, but are also associated with changes in metabolism and cardiovascular control. These associations of a GR-gene polymorphism with metabolism and cardivascular control, and also with the regulation of the HPA-axis, indicates an important underlying role of cortisol in the etiology of these complex disorders. Therefore, we propose that a common underlying defect in these complex disorders is a disregulation of the HPA-axis, especially during stress. The clinical implication is that the regulation of the HPA-axis should be envisioned as a primary target of new drugs for the treatment of stress-related disorders.

Humans↗
PubMed2005

A novel polymorphism in the 5' untranslated region of the porcine cytochrome b5 (CYB5) gene is associated with decreased fat androstenone level.

Raising intact male pigs would have a significant economic impact on the pork industry; however, the presence of 16-androstene (a major cause of boar taint) in meat from male pigs would be highly objectionable to consumers. In pigs, a positive correlation has been found between cytochrome b5 (CYB5) and production of 16-androstene. The search for polymorphism of CYB5 and functional analysis of polymorphism found should have an important impact on the efforts to develop genetic markers to select for low androstenone levels in fat from pigs. The aim of this study was to search the porcine CYB5 gene for mutations, examine its expression, identify genetic polymorphisms, and study how a genetic variation in this enzyme translates into interindividual variation in androstenone levels in fat from pig testis. We have identified a single nucleotide polymorphism (SNP) (G --> T) at base 8 up-stream of ATG in the CYB5 5' untranslated region which is associated with a lower fat androstenone level. Of the 229 testis samples tested, 84.8% were homozygous for the variant G, 12.4% were heterozygous, and 2.8% were homozygous for the variant T. Functional analysis of this mutation revealed that an individual homozygous for the T allele showed significantly lower CYB5 activity than an individual homozygous for the G allele. Thus, this may be at least partially responsible for a lower level of androstenone in pigs. Our findings provide an important genetic basis toward the goal of predicting the androstenone status in pigs and developing genetic markers for low androstenone.

5' Untranslated Regions↗
PubMed2004

Risk of coronary artery disease associated with polymorphism of the cytochrome P450 epoxygenase CYP2J2.

BACKGROUND: Cytochrome P450 (CYP) 2J2 is expressed in the vascular endothelium and metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs). The EETs are potent endogenous vasodilators and inhibitors of vascular inflammation. However, it is not known whether genetic polymorphisms of CYP2J2 are associated with increased cardiovascular risks. METHODS AND RESULTS: All 9 exons of the CYP2J2 gene and its proximal promoter were sequenced in 132 patients to identify potential variants. Functional consequence of a single nucleotide polymorphism (SNP) in the promoter of CYP2J2 was further evaluated by use of transcription factor-binding and reporter assays. A total of 17 polymorphisms were identified. One of the most relevant polymorphisms in terms of frequency and functional importance is located at -50 (G-50T) in the proximal promoter of CYP2J2. Screening of 289 patients with coronary artery disease and 255 control subjects revealed 77 individuals with the G-50T SNP (17.3% of coronary artery disease patients, 10.6% of control subjects; P=0.026). The association of the G-50T polymorphism remained significant after adjustment for age, gender, and conventional cardiovascular risk factors (OR, 2.23; 95% CI, 1.04 to 4.79). The G-50T mutation resulted in the loss of binding of the Sp1 transcription factor to the CYP2J2 promoter and resulted in a 48.1+/-2.4% decrease in CYP2J2 promoter activity (P<0.01). Plasma concentrations of stable EET metabolites were significantly lower in individuals with the G-50T SNP. CONCLUSIONS: A functionally relevant polymorphism of the CYP2J2 gene is independently associated with an increased risk of coronary artery disease.

3' Untranslated Regions↗
PubMed2003

Frequency distribution of C3435T mutation in exon 26 of the MDR1 gene in a Spanish population.

P-glycoprotein (PGP) is a transmembrane efflux transporter with an important role in drug therapy. The level of PGP expression leads to relevant consequences in terms of efficacy and toxicity by modulating drug disposition. A single nucleotide polymorphism (SNP) in exon 26 of the gene C3435T was recently associated to PGP levels and substrate uptake. Persons who were homozygous for the T-allele had significantly decreased PGP expression compared with C/C persons. Due to this fact and bearing in mind the important differences among populations regarding the frequencies of persons carrying mutations affecting drug disposition, the authors wanted to study the prevalence of this genetic trait in their population. DNA samples from 408 persons were assayed by a PCR-RFLP method. The results showed that the distributions of the C/C, T/T, and C/T genotypes in the Spanish population were 26%, 22%, and 52%, respectively. With regard the C-allele frequency, which has been studied in several populations, the result in their population was 52%, significantly lower (P < 0.0001) than that found in African populations and similar to several Asian and Caucasian (UK) populations (P > 0.05). By contrast, the C-allele frequency in southwest Asian, German, and Portuguese populations was significantly lower than in the Spanish population (P < 0.001, P < 0.01, and P < 0.05, respectively). The great differences found between their population and others, such as the African and southwest Asian populations, could have important therapeutic implications when drugs that are a substrate of PGP are used.

Adolescent↗
PubMed2006

Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia.

There is now strong evidence that Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia. NRG1 mediates some of its effects through the tyrosine kinase receptor erbB4, and analysis of gene knock-out animals suggests that the functional interaction of NRG1 and erbB4 mediates behaviors that may model some aspects of the schizophrenia phenotype in mice. Given these findings, we have sought evidence for association between schizophrenia and erbB4. Mutation screening of erbB4 in 14 DSMIV schizophrenics revealed 15 SNPs, none of which were nonsynonymous. Analysis of the allele frequencies of each SNP in pools of 368 DSMIV schizophrenics and 368 controls provided modest evidence for association with two of the SNPs, although individual genotyping in an extended sample of 680 cases did not confirm this. However, we did find evidence for a significant interaction between the NRG1 "Icelandic" schizophrenia risk haplotype and erbB4 (P = 0.019). The NRG1 and erbB4 interacting marker was further genotyped in an independent sample of 290 cases and 634 controls from Dublin. Interaction between NRG1 and erbB4 remained significant in the combined sample of 970 cases and 1,341 controls, OR = 2.98 (CI: 1.16-7.64), P = 0.01, although it only showed a trend in the Dublin sample alone (P = 0.11, two tailed). Our data require independent replication, but tentatively suggest that NRG1 may mediate its effects on schizophrenia susceptibility through functional interaction with erbB4, and that genetic interaction between variants at the two loci increases susceptibility to schizophrenia.

Adult↗
PubMed2005

Consequence of functional Nod2 and Tlr4 mutations on gene transcription in Crohn's disease patients.

The concept that mutations in germ-line encoded pattern recognition receptors with immune activating functions are associated with an increased incidence in Crohn's disease (CD) is gaining acceptance. Whether these mutations have similar or distinct effects on cellular physiology remains obscure. The incidence of three single nucleotide polymorphisms (SNPs) within the Nod2 gene and one functional SNP within both the Tlr4 and Tlr5 gene in a Dutch cohort of 637 patients with inflammatory bowel disease and 127 controls was investigated. The functional consequence of mutant NOD2 and TLR4 was investigated by comparing gene expression profiles after stimulation of monocyte-derived dendritic cells (DCs) from homozygous TLR4- and NOD2-mutant patients with lipopolysaccharides and peptidoglycan, respectively. We observed that the R702W and 1007fs Nod2 alleles and the A299G Tlr4 alleles were significantly more prevalent in patients with CD as compared to healthy controls or patients with ulcerative colitis. The phenotype of TLR4- and NOD2-mutant DCs is distinct, but a large number of genes are up- or down-regulated concordantly. These data provide a concept for the genetic basis of CD; mutations in innate immunity cause similar effects on gene transcription and finally result in comparable clinical disease presentation.

Adult↗
PubMed2006

Single nucleotide polymorphism in 5'-flanking region reduces transcription of surfactant protein B gene in H441 cells.

Surfactant protein (SP)-B is expressed in a cell-specific manner and is essential for surfactant function and survival. Abnormal surfactant function occurs in humans and genetically engineered mice with SP-B levels well below 50% of normal. SP-B mRNA levels vary in fetal lung explants among individuals, possibly due to genetic variety. Polymorphisms within the SP-B gene have been described extensively; however, some of their functional relevance remains unclear. Mutations within the SP-B gene may affect mRNA content, but altered gene transcription or mRNA-stability has not been clearly demonstrated. We characterized a single nucleotide polymorphism (SNP) found in the upstream enhancer of SP-B, consisting of a single base pair change in the consensus sequence of the most downstream-located thyroid transcription factor 1 binding element in the upstream enhancer of the SP-B 5'-flanking region and located at position 384 upstream of the transcriptional start site of the SP-B gene. In a small patient population (n = 53) we found 70% were homozygous for the wild type (WT), one individual (2%) was homozygous for the polymorphism (Pm), and 28% were heterozygous. To further elucidate possible functions we performed electromobility shift assays with extracts from H441 cells that showed a reduced binding affinity of the mutated sequence compared with WT. In reporter gene assays the Pm caused a reduction of 53% in transcriptional activity compared with WT in transfected H441 cells. Stimulation of these constructs with retinoic acid resulted in enhanced reporter gene activity of both constructs. After stimulation the Pm still exhibited a reduced activity compared with the WT sequence. We conclude that the described SNP causes differences in SP-B transcriptional activity and thus may contribute to individually different SP-B mRNA levels.

5' Flanking Region↗
PubMed2005

Low RET mutation frequency and polymorphism analysis of the RET and EDNRB genes in patients with Hirschsprung disease in Taiwan.

Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a relatively common disorder characterized by the absence of ganglion cells in the nerve plexuses of the lower digestive tract, resulting in intestinal obstruction in neonates. Mutations in genes of the RET receptor tyrosine kinase and endothelin receptor B (EDNRB) signaling pathways have been shown to be associated in HSCR patients. In this study, we collected genomic DNA samples from 55 HSCR patients in central Taiwan and analyzed the coding regions of the RET and EDNRB genes by PCR amplification and DNA sequencing. In the 55 patients, an A to G transition was detected in two (identical twin brothers). The mutation was at the end of RET exon 19 at codon 1062 (Y1062C), a reported critical site for the signaling pathways. Single nucleotide polymorphisms (SNP) in exons 2, 7, 11, 13, and 15 of RET and exon 4 of EDNRB in the HSCR patients or controls were detected. The differences between patients and controls in allele distribution of the five RET polymorphic sites were statistically significant. The most frequent genotype encompassing exons 2 and 13 SNPs (the polymorphic sites with the highest percentage of heterozygotes) was AA/GG in patients, which was different from the AG/GT in the normal controls. Transmission disequilibrium was observed in exons 2, 7, and 13, indicating nonrandom association of the susceptibility alleles with the disease in the patients. This study represents the first comprehensive genetic analysis of HSCR disease in Taiwan.

Case-Control Studies↗
PubMed2006

Thyrotoxic periodic paralysis and polymorphisms of sodium-potassium ATPase genes.

OBJECTIVE: Thyrotoxic periodic paralysis (TPP) is a complication of hyperthyroidism association with recurrent, reversible episodes of muscle weakness. Increased sodium-potassium ATPase (Na/K-ATPase) pump activity is postulated to contribute to the hypokalaemic paralytic attacks in TPP. The aim of this study was to determine the genetic predisposition to TPP in relation to Na/K-ATPase genes. DESIGN: A case-control association study. PATIENTS: Ninety-nine male Chinese TPP patients were compared to 84 male Graves' disease (GD) patients without TPP and 100 normal male controls. MEASUREMENT: A total of 1500 base pairs upstream of the transcriptional start site of the five Na/K-ATPase genes that are expressed in the skeletal muscles, namely ATP1A1, ATP1A2, ATP1B1, ATP1B2 and ATP1B4, were sequenced in all subjects for mutations or polymorphisms. The single nucleotide polymorphisms (SNPs) of the coding regions of the five genes were also studied for association with TPP. RESULTS: No mutations were detected in the 5' regions of the five genes in any of the patients studied. There was no difference in the distribution of SNPs and SNP haplotypes in the upstream and coding region of these genes between the three groups of subjects. CONCLUSION: No association between the polymorphisms of ATP1A1, ATP1A2, ATP1B1, ATP1B2 and ATP1B4 genes and TPP could be detected.

Adenosine Triphosphatases↗