Gene-environment interactions in asthma.
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Asthma↗
Biomedical subjects
R de Cid
Publications and source records attributed to R de Cid.
Met66 in the brain-derived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type.
Several lines of evidence support a role for brain-derived neurotrophic factor (BDNF) alterations in the etiology of eating disorders (EDs). BDNF heterozygous knockout mice show alterations in eating behavior, increased body weight and adipocyte hypertrophy. BDNF also regulates the synaptic efficiency through the modulation of key neurotransmitter systems previously known to be involved in ED. These findings, together with the fact that this neurotrophin is expressed in the hypothalamus nuclei associated with weight regulation and feeding control, led us to propose BDNF as a candidate gene for ED. To investigate the possible involvement of this neurotrophin in eating behavior, we screened the BDNF gene in 95 ED patients and identified four sequence variants. Two of them, -374A/T and -256G/A, were found in two patients with anorexia nervosa (AN) and consisted of single-nucleotide mutations within the 5' untranslated region (5'UTR). The other two polymorphisms resulted in a C to T transition located at the 5'UTR of the BDNF gene and an amino-acid substitution within the BDNF precursor protein (Val66Met). We performed a case-control study for these two Single-nucleotide polymorphisms in a sample of 143 ED patients and 112 unrelated controls and found a strong association of restricting AN (ANR) with the Met allele of the Val66Met BDNF polymorphism (2p=0.002). There was also evidence for a significant effect of this sequence variant on the minimum body mass index (MBMI) (2p=0.006). These results suggest that the BDNF Met66 variant may be a susceptibility factor to ED, mainly to ANR and low MBMI.
Adult↗
Erratum: Identification of five new mutations of PDS/SLC26A4 in Mediterranean families with hearing impairment.
Pendred syndrome is an autosomal-recessive disorder characterized by congenital sensorineural hearing loss combined with goiter. This disorder may account for up to 10% of cases of hereditary deafness. The disease gene (PDS/SLC26A4) has been mapped to chromosome 7q22-q31 and encodes a chloride-iodide transport protein. Mutations in this gene are also a cause of non-syndromic autosomal recessive hearing impairment (DFNB4). We have analyzed the PDS/SLC26A4 gene in Spanish and Italian families and we have detected five novel mutations (X781W, T132I, IVS2-2A>G, Y556H and 406del5).
Alleles↗
[Analysis of psoriasis susceptibility regions in the Spanish population: evidence of a major gene involved in psoriasis in the 6p21 region].
BACKGROUND: Identification of the susceptibility regions to psoriasis in Spanish population. Analysis of the chromosomal regions 6p, 17q, 4q and 1cen-q21. PATIENTS AND METHOD: Analysis of 27 Spanish families with psoriasis. Parametric and non-parametric linkage analysis with 22 polymorphic microsatellite markers in the candidate regions. RESULTS: Evidence of linkage (p < 0,05) using non-parametric methods in chromosome 6p. Absence of linkage in 17q, 4q and 1cen-q21 regions. CONCLUSION: We present the evidence of a major gene in 6p21.3 involved in psoriasis in Spanish population.
Adult↗
Identification of five new mutations of PDS/SLC26A4 in Mediterranean families with hearing impairment.
Pendred syndrome is an autosomal-recessive disorder characterized by congenital sensorineural hearing loss combined with goiter. This disorder may account for up to 10% of cases of hereditary deafness. The disease gene (PDS/SLC26A4) has been mapped to chromosome 7q22-q31 and encodes a chloride-iodide transport protein. Mutations in this gene are also a cause of non-syndromic autosomal recessive hearing impairment (DFNB4). We have analyzed the PDS/SLC26A4 gene in Spanish and Italian families and we have detected five new mutations (X871M, T132I, IVS1-2A>G, Y556H and 406del5).
Alleles↗
CFTR and asthma in the French EGEA study.
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Adolescent↗
A new approach for identifying non-pathogenic mutations. An analysis of the cystic fibrosis transmembrane regulator gene in normal individuals.
Given q as the global frequency of the alleles causing a disease, any allele with a frequency higher than q minus the cumulative frequency of the previously known disease-causing mutations (threshold) cannot be the cause of that disease. This principle was applied to the analysis of cystic fibrosis transmembrane conductance regulator (CFTR) mutations in order to decide whether they are the cause of cystic fibrosis. A total of 191 DNA samples from random individuals from Italy, France, and Spain were investigated by DGGE (denaturing gradient gel electrophoresis) analysis of all the coding and proximal non-coding regions of the gene. The mutations detected by DGGE were identified by sequencing. The sample size was sufficient to select essentially all mutations with a frequency of at least 0.01. A total of 46 mutations was detected, 20 of which were missense mutations. Four new mutations were identified: 1341+28 C/T, 2082 C/T, L1096R, and I11131V. Thirteen mutations (125 G/C, 875+40 A/G, TTGAn, IVS8-6 5T, IVS8-6 9T, 1525-61 A/G, M470V, 2694 T/G, 3061-65 C/A, 4002 A/G, 4521 G/A, IVS8 TG10, IVS8 TG12) were classified as non-CF-causing alleles on the basis of their frequency. The remaining mutations have a cumulative frequency far exceeding q; therefore, most of them cannot be CF-causing mutations. This is the first random survey capable of detecting all the polymorphisms of the coding sequence of a gene.
Cystic Fibrosis Transmembrane Conductance Regulato↗
Association study of proposed candidate genes/regions in a population of Spanish asthmatics.
A number of genes/regions have recently been reported to be linked to asthma or its related phenotypes (i.e. atopy and bronchial hyperresponsiveness), by genetic linkage and allele-sharing methods. We have performed a case-control study comparing the allelic distribution of nine microsatellite markers and two genetic variants in a group of patients attended at emergency room departments because of an acute attack of asthma with respect to an external healthy population of controls. A total of 146 asthmatic subjects and 50 population controls from Barcelona, Spain, were genotyped for nine microsatellite markers from some asthma/atopy candidate genes/regions: the beta-subunit of the high-affinity IgE receptor (Fc epsilonRI-beta) located on chromosome 11; the 5q31-32 candidate region; the T-cell receptor genes, TCR-alpha on chromosome 14 and TCR-beta on chromosome 7. Two genetic variants of the beta-subunit of the high-affinity IgE receptor (Fc epsilonRI-beta) gene were also analyzed. None of the asthmatic or control individuals carried the Ile181Leu variant. There were no significant differences between asthmatic and control subjects neither for the polymorphic markers nor for the other variant of the beta-subunit of the high-affinity IgE receptor (Fc epsilonRI-beta) gene. No association could be observed in this sample of Spanish asthmatics with the genes/regions studied.
Adult↗
Association study of the chromosomal region containing the FCER2 gene suggests it has a regulatory role in atopic disorders.
On the basis of studies with animal models, the gene for the low-affinity receptor for immunoglobulin E (IgE) (FCER2, CD23) has been implicated as a candidate for IgE-mediated allergic diseases and bronchial hyperreactivity, or related traits. Given evidence for genetic complexity in atopic disorders, we sought to study two European subpopulations, Finnish and Catalonian. We studied three phenotypic markers: (1) total serum IgE level; (2) asthma; and (3) specific IgE level for a mixture of the most common aeroallergens in Finland. Altogether, eight polymorphic markers spanning a region of 10 cM around the FCER2 gene on chromosome 19p13 were analyzed in 124 families. The physical order of the markers and the location of the FCER2 gene were confirmed by using radiation hybrids. The allele and haplotype association study showed a suggestive haplotype association (significance of p </= 0.03 based on a permutation test) for a high serum IgE response. In a subset of chromosomes segregating with asthma in families with two or more affected members, a single haplotype was found to be highly enriched (p = 8.3 x 10(-6)). However, sequence polymorphisms, which would verify structural differences in the FCER2 gene, were not detected in the coding region of the receptor. Our results suggest that chromosome 19p13 might harbor a genetic determinant of IgE-related traits. Studies in other population samples are needed to verify this finding.
Adult↗
Missense mutations in the cystic fibrosis gene in adult patients with asthma.
Asthma is a complex genetic disorder that affects 5% of adults and 10% of children worldwide. The complete characterization of the cystic fibrosis transmembrane conductance regulator (CFTR) gene identified missense mutations in 15% of 144 unrelated adult patients with asthma, but in none of 41 subjects from the general population. The four more common mutations were analyzed in an extended sample consisting of 184 individuals from the general population and did not show a significant difference in frequency. The hyperfunctional CFTR M470 allele was detected in 90% of patients with CFTR missense mutations, but in 63% of subjects from the general population and 63% of asthma patients without CFTR mutations. None of the patients with missense mutations had the 5T allele of intron 8 of CFTR, responsible for low CFTR levels, while it was detected in 8% of asthma patients without CFTR mutations and in 9% of subjects from the general population. These findings suggest a putative role for a combination of CFTR missense mutations, including the M470 allele, in the genetic variability of asthma.
Adult↗
Splice-site mutation in the PDS gene may result in intrafamilial variability for deafness in Pendred syndrome.
Pendred syndrome is a recessive inherited disorder that consists of developmental abnormalities of the cochlea, sensorineural hearing loss, and diffuse thyroid enlargement (goiter). This disorder may account for up to 10% of cases of hereditary deafness. The disease gene (PDS) has been mapped to chromosome 7q22-q31, and encodes a chloride-iodide transport protein. We performed mutation analysis of individual exons of the PDS gene in one Spanish family that shows intrafamilial variability of the deafness phenotype (two patients with profound and one with moderate-severe deafness). We identified a new splice-site mutation affecting intron 4 of the PDS gene, at nucleotide position 639+7. RNA analysis from lymphocytes of the affected patients showed that mutation 639+7A-->G generates a new donor splice site, leading to an mRNA with an insertion of six nucleotides from intron 4 of PDS. Since the newly created donor splice site is likely to compete with the normal one, variations of the levels of normal and aberrant transcripts of the PDS gene in the cochlea may explain the variability in the deafness presentation.
Amino Acid Sequence↗
Identification of SLC7A7, encoding y+LAT-1, as the lysinuric protein intolerance gene.
Lysinuric protein intolerance (LPI; OMIM 222700) is a rare, recessive disorder with a worldwide distribution, but with a high prevalence in the Finnish population; symptoms include failure to thrive, growth retardation, muscle hypotonia and hepatosplenomegaly. A defect in the plasma membrane transport of dibasic amino acids has been demonstrated at the baso-lateral membrane of epithelial cells in small intestine and in renal tubules and in plasma membrane of cultured skin fibroblasts from LPI patients. The gene causing LPI has been assigned by linkage analysis to 14q11-13. Here we report mutations in SLC7A7 cDNA (encoding y+L amino acid transporter-1, y+LAT-1), which expresses dibasic amino-acid transport activity and is located in the LPI region, in 31 Finnish LPI patients and 1 Spanish patient. The Finnish patients are homozygous for a founder missense mutation leading to a premature stop codon. The Spanish patient is a compound heterozygote with a missense mutation in one allele and a frameshift mutation in the other. The frameshift mutation generates a premature stop codon, eliminating the last one-third of the protein. The missense mutation abolishes y+LAT-1 amino-acid transport activity when co-expressed with the heavy chain of the cell-surface antigen 4F2 (4F2hc, also known as CD98) in Xenopus laevis oocytes. Our data establish that mutations in SLC7A7 cause LPI.
Adolescent↗
Functional double-negative T cells in the periphery express T cell receptor V beta gene products that cause deletion of single-positive T cells.
A proportion of peripheral T cells lack surface expression of the CD4 or CD8 coreceptor molecules and hence are designated as " double negative" (DN). Most DN T lymphocytes express the gamma/delta T cell receptor (TcR), but a minor fraction of them, in both humans and mice, express the alpha/beta TcR. Whereas alpha/beta+ DN T lymphocytes are infrequent (< 1%) in conventional lymphoid organs (spleen, blood, lymph node), they account for two-thirds of the T cells residing in adult bone marrow. Analysis of the TcR V beta repertoire expressed by peripheral DN T cells revealed a high frequency of cells bearing autoreactive TcR that cause deletion of "single-positive" (SP) (CD4+CD8-or CD4-CD8+) T cells. Peripheral DN cells thus represent a cell type that is relatively resistant to clonal deletion. Furthermore, such cells have not been inactivated (anergized) in vivo since they proliferate and secrete interleukins in response to cross-linking by monoclonal antibodies specific for these V beta gene products that are deleted in SPT cells. These results might help to understand the association of peripheral expansion of DN cells and development of autoimmune diseases.
Animals↗
Immunological self-tolerance: an analysis employing cytokines or cytokine receptors encoded by transgenes or a recombinant vaccinia virus.
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Animals↗