Missence Mutations Research Articles

Systematic profiling of Taxol resistance and sensitivity to tubulin missence mutations at molecular and cellular levels.

Taxol (paclitaxel) is the first approved microtubule-stabilizing agent (MSA) by binding stoichiometrically to tubulin, which is considered to be one of the most significant advances in first-line chemotherapy against diverse tumors. However, a large number of residue missence mutations harboring in the tubulin have been observed to cause acquired drug resistance, largely limiting the clinical application of Taxol and its analogs in chemotherapy. A systematic investigation of the intermolecular interactions between the Taxol and various tubulin mutants would help to establish a comprehensive picture of drug response to tubulin mutations in clinical treatment of cancer, and to design new MSA agents with high potency and selectivity to overcome drug resistance. In this study, we described an integration of in silico analysis and invitro assay (iSiV) to profile Taxol against a panel of 149 clinically observed, cancer-associated missence mutations in β-tubulin at molecular and cellular levels, aiming to a systematic understanding of molecular mechanism and biological implication underlying drug resistance and sensitivity conferring from tubulin mutations. It is revealed that the Taxol-resistant mutations can be classified into three types: (I) nonbonded interaction broken due to mutation, (II) steric hindrance caused by mutation, and (III) conformational change upon mutation. In addition, we identified three new Taxol-resistant mutations (C239Y, T274I, and R320P) that can largely reduce the binding affinity of Taxol to tubulin at molecular level, in which the T274I and R320P were observed to considerably impair the antitumor activity of Taxol at cellular level. Moreover, a novel drug-susceptible mutation (M363T) was also identified, which improves Taxol affinity by 2.6-fold and decreases Taxol antitumor EC50 values from 29.4 to 18.7 μM.

Characterization and map-based cloning of miniature2-m1, a gene controlling kernel size in maize

Kernel development plays an important role in determining kernel size in maize. Here we present the cloning and characterization of a maize gene, nitrate transporter1.5 (NRT1.5), which controls small kernel phenotype by playing an important role in kernel development. A novel recessive small kernel mutant miniature2-m1 (mn2-m1) was isolated from self-pollinated progenies of breeding materials. The mutant spontaneously showed small kernel character arresting both embryo and endosperm development at an early stage after pollination. Utilizing 21 polymorphic SSR markers, the mn2-m1 locus was limited to a 209.9-kb interval using 9 176 recessive individuals of a BC1 segregating population from mn2-m1/B73. Only one annotated gene was located in this 209.9 kb region, Zm00001d019294, which was predicted to encode nitrate transporter1.5 (NRT1.5). Allelism tests confirmed that mn2-m1 was allelic to miniature2-m2 (mn2-m2) and miniature2-710B (mn2-710B). The mn2-m1 and mn2-m2 alleles both had nucleotide deletions in the coding region resulting in premature termination, and the mn2-710B allele had some missence mutations. Subcellular localization showed that Miniature 2 (MN2) is localized in the plasma membrane. Quantitative real-time PCR (qRT-PCR) analysis revealed that the expression of MN2 and some genes involved in the basal endosperm transfer layer (BETL) and embryo surrounding region (ESR) development were affected in mn2-m1 seeds. These results suggested that MN2 plays an important role in maize seed development.

Molecular-Genetic Diagnostics of Angelman Syndrome – The Bulgarian Experience

Abstract Objective: The aim of the study was to determine the molecular mechanisms of mutagenesis in Bulgarian patients with Angelman syndrome (AS). AS is a severe neurodevelopmental disorder caused by loss of expression in brain of the maternally inherited UBE3A gene as a result of various 15q11.2-q13 alterations. Material and Methods: In total 24 patients (11 boys, 13 girls) from 22 unrelated families with suspected clinical diagnosis AS were analysed. We used methylation specific PCR, multiplex ligation-dependent probe amplification, methylation sensitive MLPA, and direct sequencing of the UBE3A gene. Results: In 9 families (41%) pathogenic mutations were detected, which confirmed the clinical diagnosis on а molecular-genetic level. In 4 (44%) of these families we found 15q11-q13 region deletion with breakpoints BP1-BP3 or BP2-BP3. In 1 (11%) of the families we found imprinting defect: deletion of the AS-SRO regulatory region (part of the PWS-AS imprinting center). In 1 (11%) of the families we detected a rare finding – paternal uniparental disomy of chromosome 15. In 3 (33%) of the families diff erent point mutations in the UBE3A gene were detected: two novel missence mutations c.488T > C; p.Leu163Ser and c.1832A > T; p.Gln611Leu, and one known frameshift mutation c.2576_2579delAAGA; p.Lys859Argfs*4. Conclusion: The obtained results helped us to develop a systematic diagnostic algorithm in order to provide proper diagnosis for the patients with AS. Combining excellent knowledge of the molecular mechanisms of mutagenesis and proper molecular-genetic testing approaches is a cornerstone in the management of AS patients, ensuring AS families would receive both adequate genetic counseling and prophylaxis of the disease in the future.

Systematic molecular profiling of inhibitor response to the clinical missense mutations of ErbB family kinases in human gastric cancer

The oncogenic receptor tyrosine kinase family ErbB consists of four members (ErbB1, ErbB2, ErbB3 and ErbB4); they are involved in the tumorgenesis of diverse cancers. A variety of missence mutations have been clinically observed in ErbB kinases, which would shift drug sensitivity to these kinases and cause drug resistance in targeted cancer therapy. In this study, systematic inhibitor response to ErbB missense mutations in gastric cancer (GC) is investigated by combining computational analysis and experimental assay. The response profile is created for 6 ATP-competitive, reversible inhibitors against 9, 17, 5 and 17 GC-associated missense mutations of ErbB1, ErbB2, ErbB3 and ErbB4 kinase domains, respectively. From the profile a number of potential resistant and sensitive responses are identified theoretically. It is suggested that most ErbB mutations have only a modest effect on inhibitor binding, but few that are located around the kinase active site can influence the binding significantly. Structural examination reveals that steric hindrance and allosteric effect are primarily responsible for inhibitor resistance and sensitivity, respectively. Two ErbB2 mutations, namely V777L and T862A, are predicted to cause effective resistance on inhibitors TAK285 and Lapatinib, respectively. Kinase assays consistently observe that the mutations can reduce inhibitor activity by 4.9-fold and 2.4-fold, with IC50 changing from 29 to 16 nM (wild type) to 83 and 39 nM (mutant) for TAK285 and Lapatinib, respectively.

Systematic profiling of clinical missence mutation effects on the intermolecular interaction between human growth hormone and its receptor in isolated growth hormone deficiency

Isolated growth hormone deficiency (IGHD) is the most common pituitary hormone deficiency and can result from congenital or acquired causes. Among the known factors, genetic mutations in human growth hormone (hGH) remain the most frequent cause of IGHD, which influence the binding of hGH to its cognate receptor (hGHbp). Although previous studies have systematically investigated the residue importance at hGH–hGHbp complex interface, the molecular role of IGHD-associated residue mutations in the complex function still remains largely unexplored. Here, a total of 21 known hGH naturally-occurring missence mutations that have been clinically observed to be involved in IGHD disorder are collected and confirmed by original literature; they effects on the conformation, energetics and dynamics of hGH–hGHbp recognition and interaction are dissected at molecular level by using atomistic dynamics simulations, binding energy calculations and fluorescence spectroscopy assays. A systematic profile of hGH–hGHbp binding response to these clinical missence mutations is created, based on which it is revealed that (i) most mutations have appreciably unfavorable effect on the binding, which potentially destabilize the complex interaction, while only very few are predicted as moderate stabilizers for the complex system, and (ii) these disease-related mutations can locate either at complex interface or in hGH protein interior far away from the interface; both can influence the complex binding through either direct interaction or indirect allostericity. Two mutations, E100K (non-interface) and G146R (interface), are identified to address potent destabilization effect on hGH–hGHbp complex system; they can reduce the complex binding affinity by 8-fold (Kd changes from 0.76 to 5.9 nM) and 46-fold (Kd changes from 0.76 to 34.7 nM), respectively.

Genetics of hypophosphatasia

Hypophosphatasia (HPP) is a rare inherited disorder primarily affecting bone and dental mineralization. Although there is a continuum in the severity of the disease, clinical forms may be arbitrarily distinguished on the basis of age at onset and the presence or absence of bone symptoms: perinatal, infantile, juvenile, adult, prenatal benign, and odontological. Severe forms (perinatal and infantile) are autosomally recessively inherited while less severe forms may be autosomally recessively or dominantly inherited. Genetic counseling is complicated by the coexistence of the two modes of inheritance, the incomplete penetrance of the dominant forms, the markedly variable expression of the disease, including intra-familial expression, and the existence of a benign prenatal form that may sometimes be difficult to distinguish from the severe prenatal form. The disease is due to loss-of-function mutations in the Alkaline Phosphatase-Liver (ALPL) gene encoding the tissue nonspecific alkaline phosphatase (TNSALP). The great variety of missence mutations and the dominant negative effect of some mutations largely explain the clinical heterogeneity. Directed mutagenesis studies allowed further elucidation of the cellular pathophysiology of HPP, classification of the alleles in terms of their severity and dominant negative effect, and molecular explanations of the dominant inheritance mode. Genetics significantly contributed to show that there are in fact two HPPs, rare, severe and recessive HPP, and mild recessive or mild dominant HPP, which is markedly more frequent and probably under-diagnosed. The prevalence of the severe forms of HPP has been estimated to be 1/300,000 in France and Northern Europe while the prevalence of the moderate forms of HPP may reach 1/6,370.

MOLECULAR MECHANISMS OF BRUGADA SYNDOME SUBTYPE 1

Brugada syndrome is a rare hereditary arrhythmogenic disorder first described by Brugada brothers in 1992. Despite the large amount of clinical and experimental data, there is no complete understanding of genotype-phenotype relation in pathogenesis of the disease caused by missence mutations in SCN5A, which encodes the alpha-subunit of the major cardiac voltage-gated sodium channel Nav 1.5. The aim of this review is to summarize current knowledge on molecular, cellular and ionic mechanisms of the Brugada syndrome development. We focused on the clinical picture and physiological consequences of decreasing activity of Nav 1.5 and analyzed the impact of biophysical properties alterations on the pathological state. The mutation-specific influence of pharmacological agents and signalling proteins was described.

Metastatic gastrointestinal stromal tumour of the ileum with dual primary c-KIT missence mutations

Metastatic gastrointestinal stromal tumour of the ileum with dual primary c-KIT missence mutations

OP095: Novel TP53 coding region mutation in the patients of oral squamous cell carcinoma (OSCC) of Pakistan

Purpose The major risk factor for developing OSCC in countries like Pakistan is the excessive chewing habit of paan (betel quid), chhaliya (betel nut), tobacco, niswar (type of dipping tobacco, made from fresh tobacco leaves, calcium oxide, and wood ash), gutka (the preparation of crushed betel nut, tobacco, catechu, lime, saffron, spices, menthol, and sweet or savory flavors), and manpuri (the powder of betel nut, tobacco and slaked lime). It has been reported that exon 4–9 were the hot spots of the mutation in TP53. This study aims to find out the loss of TP53 functions due to mutation/polymorphism caused by genomic alteration and interaction with tobacco and its related ingredients in Pakistan. Materials and methods A total of 260 OSCC patient’s tissue and blood specimens were collected with informed consent from local hospitals of Karachi and compared with blood samples of 260 age and sex matched controls. Mutations in exons 2–11 of TP53 were examined by polymerase chain reaction and single stranded conformational polymorphisms (PCR-SSCP). The samples showing mobility shift were purified and directly sequenced. Results The novel “AGT” to “ACT” missence mutation was identified at position 719 in exon 7 ofTP53. This change substitutes the amino acid serine with threonine at position 240 of p53 protein suggesting that the threonine allele of p53 gene is associated with mutation in conserved region. This mutation was observed in the tumors of the OSCC patients. The blood samples of the patients and the controls have not shown the nucleotide change in this region. Conclusions This novel missence mutations in DNA binding domain indicated that the DNA structure may be damaged by the use of exogeneous DNA-damaging agents including tobacco related carcinogens present in gutka, niswar and manpuri, which may result in the loss of cellular processes and p53 protein function.

Homozygosity for two missense mutations in the leptin receptor gene (P316T;W646C) in a Turkmenian girl with severe early-onset obesity

Leptin receptor gene mutations are a very rare cause of severe early-onset obesity. They are also associated with lack of pubertal development and intense hyperphagia. Presented here is a case of a 6-year-old Turkmenian girl with monogenic obesity due to a congenital deficiency of the leptin receptor. She was born from a consanguineous marriage of second cousins after 40 gestational weeks following an uncomplicated pregnancy. Her birth weight was 3500 g. However, rapid weight gain was observed after 6 months. On presentation she was 130 cm tall [> 97th percentile; standard deviation score (SDS): +2], with a weight of 90 kg (> 97th percentile; SDS: +5.3) and a body mass index (BMI) of 53.2 kg/m2 (SDS: +3.6). Results of genetic evaluation revealed the patient to be homozygous for two missense mutations in the leptin receptor gene (P316T;W646C) resulting in complete loss of leptin receptor function. Both parents were heterozygous for the same pair of missence mutations.

Genetic variations in the regulation of energy balance

Single nucleotide polymorphism (SNP) near certain genes revealed association of FAT (fat mass and obesity-associated gene), MC4R (melanocortin 4 receptor gene), and other genes with obesity. However, involvement of the FAT expression products in the regulation of energy balance remains to be clarified. The function of MC4R encoding melanocortin 4 receptor (MC4R) is somewhat better understood. α-, β-, and γ- MSH encoded by the POMC gene bind to MC4R, reduce food intake, and slow down fat accumulation. Expression of POMC encoding MSH is enhanced by leptin binding to its receptor (LepRb) in hypothalamic neurons. Mutations in human and animal MC4R, POMC, and LEP genes are associated with obesity. More than 60 mutations in MC4R, more than 20 mutations in POMC and fewer LEP mutations have been reported. Nonsense mutations and reading frame shifts block gene expression and thereby disrupt protein synthesis. Missense mutations frequently affect protein folding in endoplasmic reticulum; unfolded or misfolded proteins remain in the cytoplasm and undergo degradation. Certain missence mutations do not interfere with gene expression and folding of proteins but impair their functioning at the periphery. p.S127L mutation in MC4R, p.E206X and p.F144L mutations in POMC as well as other mutations in homozygous and heterozygous forms account for impaired energy balance in humans. The following mutations have been identified in the LEP gene: G133fsX15, p.R105X, p.R105W, and p.S141C mutations. In homozygous form they are associated with obesity and other pathological conditions.

PITPNM3 is an uncommon cause of cone and cone-rod dystrophies

The first mutation in PITPNM3, a human homologue of the Drosophila retinal degeneration (rdgB¬¬) gene was reported in two large Swedish families with autosomal dominant cone dystrophy. To establish the global impact that PITPNM3 has on retinal degenerations we screened 163 patients from Denmark, Germany, the UK, and USA. Four sequence variants, two missence mutations and two intronic changes were identified in the screen. Thus, mutations in PITPNM3 do not appear to be a major cause of cone or cone-rod dystrophy.

Mutation analysis of ATP2C1 gene in patients with Hailey-Hailey disease

Objective To detect the mutations in ATP2C1 gene of 5 sporadic patients with Hailey-Hailey disease (HHD).Methods Five sporadic patients with HHD collected from the outpatient clinic setting were recruited into this study with informed consent.Blood samples were taken from all patients and 100 unrelated human controls.and DNA was extracted from these samples.Mutation scanning was carried out for ATP2C1 gene by polymerase chain reaction (PCR) and direct sequencing.Results The diagnosis of all cases was confirmed by typical clinical manifestation,cutaneous pathology and immunofluorescence pathology.Five novel mutations.including a deletion mutation (2025delG),three missence mutations (L269R,C348R,A651D) and a non-sense mutation (Q259X) were identified in these cases.No mutations were detected in any of the 100 controls.Conclusion Five novel mutations in ATP2C1 gene have been identified for Hailey-Hailey disease. Key words: Pemphigus,benign familial; Genes,ATP2C1; Mutation

Human tissue distribution of paraoxonases 1 and 2 mRNA

We have studied the distribution of mRNA for paraoxonases (PON) 1 and 2 in 24 human tissues using Gene Expression Panels. PON1 mRNA was restricted to adult kidney, liver, and colon as well as fetal liver, whereas PON2 mRNA was more widely distributed in adult human brain, heart, kidney, spleen, liver, colon, lung, small intestine, muscle, stomach, testis, placenta, salivary, thyroid and adrenal glands, pancreas, skin, and bone marrow, as well as fetal brain and liver. PON2 mRNA was not found in ovary, uterus, or plasma leukocytes using the panels. However, using real time PCR, we found PON2 mRNA expression in human plasma leukocytes. There were differences between the tissue distribution of mRNAs found in this study and the immunohistochemical localization of the PON1 and PON2 proteins reported previously. In particular, PON1 protein is much more widely distributed than its mRNA, possibly indicating the delivery of PON1 to various tissues by HDL. In addition, differences between PON2 mRNA and protein distributions could be due to missence mutations in the PON2 gene, causing nontranslation of mRNA to protein in some tissues.

Abstract 3065: Loss of ARL11 function promotes growth of in situ neoplasia by activating the ras pathway

Abstract Our previously reported whole-organ genome-wide mapping studies of bladder cancer provided evidence that a new class of genes, referred to as forerunner (FR) genes (ITM2B, P2RY5, GPR38 and ARL11), located near known tumor suppressors such as RB1, may drive early clonal expansion of neoplasia. (S Lee, et al. PNAS 104: 13732-13737, 2007; T Majewski et al. Lab Inv 88: 694-712, 2008) These studies suggested three major steps for the involvement of the RB1 locus in tumor development. In the first step, one allele of FR gene and RB1 is inactivated by large deletions. In the second step, homozygous inactivation of the FR genes is accomplished by hypermethylation or less frequently by missence mutations. Homozygous inactivation of FR genes is associated with the clonal expansion of in situ lesions referred to as low-grade intraurothelial neoplasia. In the final, third step, the contiguous tumor suppressor, such as RB1, is inactivated most commonly by a mutation. This step is associated with clonal evolution into a transformed phenotype with microscopic features of carcinoma in situ progressing to invasive cancer. Recently, we concentrated our efforts on the ARL11 candidate FR gene, which encodes ADP-ribosylation factor-like 11 protein, a ras-related member of the small GTPases, that functions as GDP/GTP nucleotide interswitch for signal transduction. We have shown that it has been silenced by hypermethylation in approximately 40% of urothelial carcinomas of the bladder and the silencing was associated with in situ expansion of intraurothelial neoplasia. Moreover, loss of ARL11 expression was almost mutually exclusive with the FGFR3 mutations (<5% of bladder tumors showed a co-existence of mutant FGFR3 and methylated ARL11). Functional studies conducted on immortalized normal urothelial cells grown in vitro showed that ARL11 reduced cell proliferation, which was mediated by the inhibition of the ras pathway. This effect was associated with the down-regulation of the active ras and ERK1/2 phosphorylation as well as with the up-regulation of negative cell cycle regulator proteins such as p27kip1 and parallel down-regulation of cyclins D1 and E. Conversely, the silencing of ARL11 conferred a tumor suppressor effect promoting cell proliferation via the activation of the ras signaling pathway. In summary, our studies show that recessive events in the RB1 locus associated with the loss of ARL11 function promote clonal expansion of intraurothelial precursor lesions by activating the ras pathway in early occult phases of human bladder carcinogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3065.

Genetic variations in the regulation of energetic balance

Single nucleotide polymorphism (SNP) near certain genes revealed association of FAT (fat mass and obesity-associated gene), MC4R (melanocortin 4 receptor gene), and other genes with obesity. Participation of the FAT expression products in the regulation of energy balance remains to be clarified. The function of MC4R encoding melanocortin 4 receptor (MC4R) is somewhat better understood. α-, β-, and γ-MSH encoded by the POMC gene bind to MC4R, reduce food intake, and slow down fat accumulation. Expression of POMC that codes MSH is enhanced by leptin binding to the receptor (LepRb) in hypothalamic neurons. Mutations in human and animal MC4R, POMC, and LEP genes are known to be associated with obesity. More than 60 mutations in MC4R, more than 20 mutations in POMC and fewer LEP mutations have been reported. Nonsense mutations and reading frame shifts block gene expression and thereby disrupt protein synthesis. Missense mutations frequently affect protein folding in endoplasmic reticulum; unfolded or misfolded proteins remain in the cytoplasm and undergo degradation. Certain missence mutations do not interfere with gene expression and folding of proteins but impair their functioning at the periphery. P.S127L mutation in MC4R, p.E206X and p.F144L mutations in POMC as well as other mutations in homozygous and heterozygous forms account for disturbed energy balance in man. The LEP gene has been reported to contain G133fsX15, p.R105X, p.R105W, and p.S141C mutations. As a rule, they are associated with obesity and other pathological conditions only in homozygous forms.

Hb Southern Italy: coexistence of two missence mutations (the Hb Sun Prairie α2 130 Ala > Pro and Hb Caserta α2 26 Ala > Thr) in a single HBA2 gene

Hb Southern Italy: coexistence of two missence mutations (the Hb Sun Prairie α2 130 Ala &gt; Pro and Hb Caserta α2 26 Ala &gt; Thr) in a single <i>HBA2</i> gene

Hb Southern Italy: coexistence of two missence mutations (the Hb Sun Prairie α2 130 Ala → Pro and Hb Caserta α2 26 Ala → Thr) in a single HBA2 gene

This study describes a new molecular condition in the alpha(2)-globin gene (HBA2) found in six unrelated families from Southern Italy (Campania and Sicily). This new double mutant form of haemoglobin is called Hb Southern Italy and originated from the coexistence of two known mutations occurring in the same globin gene, HBA2 26 G-->A (Hb Caserta) and HBA2 130 G-->C (Hb Sun Prairie). Hb Sun Prairie was originally observed in Indian patients in either the homozygous state, with severe hemolytic anemia, and in the heterozygous state with microcytosis, or in asymptomatic cases as an alpha-thalassemia carrier phenotype. Hb Caserta was observed for the first time in a Casertian family (South Italy) that displayed a slowmigrating haemoglobin upon investigation. We report the clinical phenotype and molecular study of this new double mutant form of haemoglobin in heterozygous and homozygous subjects, as well as in association with alpha degrees delectional thalassemia.

A Novel Mechanism of Vascular Smooth Muscle Cell Regulation by Notch

See related article, pages 1483–1491 The Notch family of receptors, Notch1 to -4, are heterodimer transmembrane proteins, consisting of an extracellular domain and a noncovalently linked intracellular domain (ICD). Upon interaction with the DSL family of proteins (Jagged, Delta-like) on neighboring cells, Notch undergoes proteolytic cleavage, which frees the ICD from the plasma membrane. This results in translocation of the ICD into the nucleus, where it forms a complex with the CSL family of transcriptional repressors (CBF1/RBP-Jk), removing the repression and allowing for target gene (Hes, Hey) transcription.1,2 Tissue distribution of the Notch proteins varies widely. Notch1 and -4 are predominantly endothelial, prominent in both arteries and veins, and present in all stages of development (embryonic to adult); the expression of Notch2 is typically confined to pulmonary endothelium, but Notch3 is primarily expressed in adult arterial vascular smooth muscle cells (VSMCs) in large conduit, pulmonary, and systemic resistance arteries.3 This specific pattern of temporal and spatial distribution correlate to diverse functions of the Notch family in vascular development and physiology in vertebrates reported to date.4 In the cardiovascular system, Notch signaling plays a role in several aspects of vascular development, including vasculogenesis, angiogenesis, differentiation, vascular remodeling, and VSMC maturation. Notch1 and -4 signaling appears critical in vasculogenesis and angiogenesis during early development, when it interacts with vascular endothelial growth factor signaling to specify artery–vein differentiation of endothelial cells (ECs). Transgenic mice deficient for Notch1 fail to undergo embryonic angiogenic remodeling, and vascular development is arrested at the primitive undifferentiated plexus, resulting in an embryonic lethal phenotype. Notch2-null mutations likewise result in embryonic lethality characterized by multiple large and small vessel aneurysms. Notch4 deletion results in no obvious phenotypic alteration. Notch3−/− mice are viable; however, they fail to develop proper arterial VSMC phenotype, resulting in vein-like …

Association of interleukin 8 receptor alpha polymorphisms with chronic obstructive pulmonary disease and asthma

Chronic obstructive pulmonary disease (COPD) and asthma are common complex diseases characterized by airflow obstruction and inflammatory processes in the small airways. Interleukin 8 (IL-8) is a potent pro-inflammatory cytokine which interacts with the receptors interleukin 8 receptor α (IL8RA, CXCR1) and interleukin 8 receptor β (IL8RB, CXCR2), leading to activation and migration of leukocytes. In order to evaluate the role of the IL8RA gene in the pathogenesis of COPD and asthma, we screened the coding region of IL8RA for mutations by means of single strand conformation polymorphism (SSCP) analysis in 50 probands and identified three missence mutations (M31R, S276T and R335C). Then were these three polymorphisms genotyped in 182 adult patients with COPD, 68 adult patients and 130 children with asthma and 454 healthy controls. The frequencies of the IL8RA 31R and 335C alleles were significantly increased in patients with COPD and in children with asthma compared to healthy controls (p=0,0073 and p=0,023, respectively). Thus, these polymorphisms may play a role in the pathogenesis of COPD and asthma.