Localization of a gene for Mobius syndrome to chromosome 3q by linkage analysis in a Dutch family

Mobius syndrome (MIM no. 157900) consists of a congenital paresis or paralysis of the VIIth cranial nerve, frequently accompanied by paralysis of other cranial nerves, orofacial and limb malformations, defects of the musculoskeletal system and mental retardation. Although most patients are sporadic cases, familial recurrence is not rare. Different pedigrees suggest different modes of inheritance. We performed linkage analysis in a large family with autosomal dominantly inherited Mobius syndrome, consisting essentially of asymmetric bilateral facial pareses. After exclusion of the candidate region for Mobius syndrome on 13q12.2-q13, we localized the gene to chromosome 3q21-22, indicating genetic heterogeneity of Mobius syndrome. This heterogeneity is further proven by the exclusion of both loci in a second family with Mobius syndrome.      

Olfactory receptor gene cluster on human chromosome 17: possible duplication of an ancestral receptor repertoire

A gene superfamily of olfactory receptors (ORs) has recentlybeen identified in a number of species. These receptors sharea seven transmembrane domain structure with many neurotransmitterand hormone receptors, and are likely to underlie the recognitionand G-protein-mediated transduction of odorant signals. Previously,OR genes cloned in different species were from random locationsin the respective genomes. We report here the cloning of 16human OR genes, all from chromosome 17(17p 13.3). The intronlesscoding regions are physically mapped (on 35 cosmids) in one0.35Mb long contiguous cluster, with an average intergenic separationof 15kb. The human OR genes in the cluster belong to four differentgene subfamilies, displaying as much sequence variability asany randomly selected group of ORs. This suggests that the clusteridentified may be one of several copies of an ancestral OR generepertoire whose existence may predate the divergence of mammals.The latter may have duplicated In some specles to form the presentmammalian OR gene repertoire, with several hundred genes. Thehuman chromosome 17 OR gene cluster may thus be a good modelfor understanding human olfeaction, as well as the ontogenyand phylogeny of the OR gene superfamlly.     

No linkage and association of atopy to chromosome 16 including the interleukin-4 receptor gene

BACKGROUND: Several susceptibility genes for atopy have been suggested in recent years. Few have been investigated as intensively as the interleukin-4-receptor alpha (IL4Ralpha) gene on chromosome 16. The results remain in dispute. Therefore, in a robust design, we tested for association of type I allergy to the IL4R variations I50V and Q576R, and investigated chromosome 16 for atopy candidate regions in general. METHODS: We identified 100 Danish allergy sib-pair families. Five conservative phenotypes for type I allergy were defined and evaluated. The IL4R variations were genotyped in trios and evaluated by the transmission disequilibrium test (TDT). Multipoint linkage analysis and exclusion mapping were conducted with sib-pairs analyzed for 17 microsatellite markers. RESULTS: No evidence for association or linkage to the IL4R polymorphisms was found (P values: 0.12-0.90). Linkage analysis did not support linkage of any of the phenotypes to chromosome 16. Major parts of chromosome 16 were excluded as candidate regions harboring oligogenes for type I allergy. CONCLUSION: We found chromosome 16 unlikely to harbor strong candidate genes for type I allergy. The role of the IL4Ralpha gene in the inheritance of atopy was insignificant in the Danish population. The use of conservative allergy phenotypes in the search for genes predisposing to atopic disease was discussed.     

Organization of the chemokine gene cluster on human chromosome 17q11.2 containing the genes for CC chemokine MPIF-1, HCC-2, HCC-1, LEC, and RANTES.

To understand the organization of the human CC chemokine gene cluster on chromosome 17q11.2, we determined the nucleotide sequence of a region 181 kb long containing five CC chemokine genes, MPIF-1 (SCYA23), HCC-2 (SCYA15), HCC-1 (SCYA14), LEC (SCYA16), and RANTES (SCYA5), by the random shot-gun method. The four CC chemokine genes, MPIF-1, HCC-2, HCC-1, and LEC, are clustered within a region 40 kb long, whereas the RANTES gene is located approximately 10 kb apart from the four chemokine gene minicluster. These chemokine genes are arranged in the same orientation, and their sizes are relatively long, 3.1 (HCC-1)-8.8 kb (RANTES) when compared with other CC chemokine genes, such as MIP-1alpha/LD78alpha (SCYA3) (1.9 kb) and MCP-1 (SCYA2) (1.5 kb). In contrast to most other human CC chemokine genes that consist of three exons, the MPIF-1 and HCC-2 genes, separated by 12 kb, have four exons. When the nucleotide sequences of the MPIF-1 and HCC-2 genes are compared, they are well conserved, including introns and flanking sequences, except for the middle region of the long first intron, indicating that they have been generated recently in evolutionary terms by duplication. In addition to the CC chemokine genes, more than 30 exons are identified in the sequenced region by similarity search against expressed sequence tags (ESTs) and also by the gene prediction program GenScan. This indicates that the chemokine cluster sequenced in this study is a gene-rich region in the human genome.     

GABA-A receptor beta3 and alpha5 subunit gene cluster on chromosome 15q11-q13 and bipolar disorder: a genetic association study

There is accumulated evidence that the genes coding for the receptor of gamma aminobutyric acid (GABA), the most important inhibitory neurotransmitter in the CNS, may be involved in the pathogenesis of affective disorders. In a previous study, we have found a genetic association between the GABA-A receptor alpha5 subunit gene locus (GABRA5) on chromosome 15q11-of 13 and bipolar affective disorder. The aim of the present study was to examine the same subjects to see if there exists a genetic association between bipolar affective disorder and the GABA receptor beta3 subunit gene (GABRB3), which is located within 100 kb from GABRA5. The sample consisted of 48 bipolar patients compared to 44 controls (blood donors). All subjects were Greek, unrelated, and personally interviewed. Diagnosis was based on DSM-IV and ICD-10 criteria. The marker used was a dinucleotide (CA) repeat polymorphism with 12 alleles 179 to 201 bp long; genotyping was successful in all patients and 43 controls. The distribution of GABRB3 genotypes among the controls did not deviate significantly from the Hardy-Weinberg equilibrium. No differences in allelic frequencies between bipolar patients and controls were found for GABRB3, while this locus and GABRA5 did not seem to be in significant linkage disequilibrium. In conclusion, the GABRB3 CA-repeat polymorphism we investigated does not present the observed association between bipolar affective illness and GABRA5. This could be due to higher mutation rate in the GABRB3 CA-repeat polymorphism, but it might also signify that GABRA5 is the gene actually associated with the disease.     

Exclusion of linkage to the CDL1 gene region on chromosome 3q26.3 in some familial cases of Cornelia de Lange syndrome

Cornelia de Lange Syndrome (CdLS) is a complex developmental disorder consisting of characteristic facial features, limb abnormalities, hirsutism, ophthalmologic involvement, gastroesophageal dysfunction, hearing loss, as well as growth and neurodevelopmental retardation. Most cases of CdLS appear to be sporadic. Familial cases are rare and indicate autosomal dominant inheritance. Several individuals with CdLS have been reported with chromosomal abnormalities, suggesting candidate genomic regions within which the causative gene(s) may lie. A CdLS gene location (CDL1) has been assigned to 3q26.3 based on phenotypic overlap with the duplication 3q syndrome (critical region 3q26.2-q27) and the report of a CdLS individual with a balanced de novo t(3;17)(q26.3;q23.1). It has been postulated that a gene within the dup3q critical region results in the CdLS when deleted or mutated. We have performed a linkage analysis to the minimal critical region for the dup3q syndrome (that encompasses the translocation breakpoint) on chromosome 3q in 10 rare familial cases of CdLS. Nineteen markers spanning a region of approximately 40 Mb (37 cM) were used. Results of a multipoint linkage analysis demonstrated total lod-scores that were negative across the chromosome 3q26-q27 region. In 4/10 families, lod-scores were less than -2 in the 2 cM region encompassing the translocation, while in the remaining 6/10 families, lod-scores could not exclude linkage to this region. These studies indicate that in some multicase families, the disease gene does not map to the CDL1 region at 3q26.3.     

A family of episodic ataxia type 2: no evidence of genetic linkage to the CACNA1A gene

Episodic ataxia type 2 (EA2) has been reported to result from mutations in the CACNA1A gene, located on chromosome 19p13. We describe a family with episodic ataxia, clinically indistinguishable from EA2, that was not caused by CACNA1A gene mutation. The proband is an 11-year-old boy, who has had 6 cerebellar ataxic attacks since 8 years of age. His attacks occurred almost monthly, lasting for 2 to 3 days. He was treated successfully with acetazolamide. His identical twin, mother and grandmother developed ataxic attacks at age 10, 34, and 50, respectively. The symptoms in his grandmother improved gradually without medication. His mother and identical twin took acetazolamide with a good response. We examined the CACNA1A gene for this family but did not detect any mutations. Furthermore, there was no evidence of genetic linkage between the CACNA1A gene and the symptomatic patients in this family. This suggests that the cause of EA2 can be heterogeneous, that is, defects of genes other than CACNA1A might be the cause of EA2.     

Coeliac disease: follow-up linkage study provides further support for existence of a susceptibility locus on chromosome 11p11

Susceptibility to coeliac disease has a strong genetic component. The HLA associations have been well described but it is clear that other genes outside this region must also be involved in disease development. Two previous genome-wide linkage studies using the affected sib pair method produced conflicting results. Our own family based linkage study of 16 highly informative pedigrees identified 17 possibly linked regions, each of which produced a result significant at p < 0.05 or less.
We have now investigated these 17 regions in a larger set of pedigrees using more finely spaced markers. Fifty multiply affected families were studied, comprising the 16 pedigrees from the original genome screen plus 34 new highly informative pedigrees. A total of 128 microsatellite markers were genotyped with an average spacing between markers of 5 cM. Two-point and three-point linkage analysis using classical and model free methods identified five potential susceptibility loci with heterogeneity lod scores > 2.0, at 6p12, 11p11, 17q12, 18q23 and 22q13.3. The most significant was a heterogeneity lod of 2.6 at D11S914 on chromosome 11p11. This marker maps to a position implicated in one of the two previous genome scans and taken together these results provide strong support for the existence of a susceptibility locus in this region.     

Relationship between chemokine receptor expression,chemokine levels and HIV‐1 replication in the lungs of persons exposed to Mycobacterium tuberculosis

Increased susceptibility to tuberculosis following HIV‐1 seroconversion contributes significantly to the tuberculosis epidemic in sub‐Saharan Africa. Lung‐specific mechanisms underlying the interaction between HIV‐1 and Mycobacterium tuberculosis infection are incompletely understood. Here we address these questions by examining the effect of HIV‐1 and latent M. tuberculosis co‐infection on the expression of viral‐entry receptors and ligands in bronchoalveolar lavage (BAL) of HIV‐1‐infected and ‐uninfected patients with and without latent M. tuberculosis infection. Irrespective of HIV‐1 status, T cells from BAL expressed higher levels of the beta‐chemokine receptor (CCR)5 than peripheral blood T cells, in particular the CD8⁺ T cells of HIV‐1‐infected persons showed elevated CCR5 expression. The concentrations of the CCR5 ligands RANTES and MIP‐1β were elevated in the BAL of HIV‐1‐infected persons compared with that in HIV‐1‐uninfected controls. CCR5 expression and RANTES concentration correlated strongly with HIV‐1 viral load in the BAL. In contrast, these alterations were not associated with M. tuberculosis sensitisation in vivo, nor did M. tuberculosis infection of BAL cells ex vivo change RANTES expression. These data suggest ongoing HIV‐1 replication predominantly drives local pulmonary CCR5⁺ T‐cell activation in HIV/latent M. tuberculosis co‐infection.     

GABA‐A receptor β3 and α5 subunit gene cluster on chromosome 15q11–q13 and bipolar disorder: A genetic association study

There is accumulated evidence that the genes coding for the receptor of gamma aminobutyric acid (GABA), the most important inhibitory neurotransmitter in the CNS, may be involved in the pathogenesis of affective disorders. In a previous study, we have found a genetic association between the GABA‐A receptor α5 subunit gene locus (GABRA5) on chromosome 15q11–of 13 and bipolar affective disorder. The aim of the present study was to examine the same subjects to see if there exists a genetic association between bipolar affective disorder and the GABA receptor β3 subunit gene (GABRB3), which is located within 100 kb from GABRA5. The sample consisted of 48 bipolar patients compared to 44 controls (blood donors). All subjects were Greek, unrelated, and personally interviewed. Diagnosis was based on DSM‐IV and ICD‐10 criteria. The marker used was a dinucleotide (CA) repeat polymorphism with 12 alleles 179 to 201 bp long; genotyping was successful in all patients and 43 controls. The distribution of GABRB3 genotypes among the controls did not deviate significantly from the Hardy‐Weinberg equilibrium. No differences in allelic frequencies between bipolar patients and controls were found for GABRB3, while this locus and GABRA5 did not seem to be in significant linkage disequilibrium. In conclusion, the GABRB3 CA‐repeat polymorphism we investigated does not present the observed association between bipolar affective illness and GABRA5. This could be due to higher mutation rate in the GABRB3 CA‐repeat polymorphism, but it might also signify that GABRA5 is the gene actually associated with the disease. © 2001 Wiley‐Liss, Inc.     

Polymorphisms of the σ1 receptor gene in schizophrenia: An association study

Possible involvement of σ receptors in the pathogenesis of schizophrenia has been suggested. In this study we searched systematically for polymorphisms in the 5′‐franking region of the σ₁ receptor. Genetic variation in this region could reduce the expression of the gene, and this suggestion is compatible with findings of reduced σ binding sites in several cortical regions of schizophrenia. We confirmed G−241T and G−240T polymorphisms; these two consecutive polymorphisms were resolved to be in complete linkage disequilibrium with each other by single‐strand conformation polymorphism (SSCP) analysis. We also identified the A61C (Gln2Pro) polymorphism, which was in almost complete linkage disequilibrium with G−241T/G−240T. There was no significant difference in the distribution of alleles or overall genotypes of the polymorphisms between schizophrenic patients (n = 129) and controls (n = 140). We found slight increased homozygosity for T−241/T−240 and C61 in patients compared with controls using multiple comparison (p = 0.045). However, the significance did not remain when a Bonferroni correction was made (p = 0.135). These results do not support that the σ₁ receptor gene plays a major role in the pathogenesis of schizophrenia. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:118–122, 2000. © 2000 Wiley‐Liss, Inc.     

Interferons as gene activators: a cluster of six interferon-activatable genes is linked to the erythroid alpha-spectrin locus on murine chromosome 1

Several interferon-activatable murine genes were mapped to murine chromosomes by hybridizing cDNA probes to Southern blots of genomic DNA samples from a panel of mouse-hamster somatic cell hybrid lines. The 12 gene is located on chromosome 12 and it specifies a 3.6-kb mRNA. The 204 gene (specifying a 2.5-kb mRNA), and three genes of the 203 gene family (hybridizing to five mRNAs of sizes between 2 and 4.5 kb), together with the 202 gene (specifying a 2-kb mRNA) are located on murine chromosome 1. By restriction fragment length polymorphism analysis of DNA samples prepared from a panel of recombinant inbred mouse lines (C57BL/6J D DBA/2J) and from 85 [C3H/HeJ-gld/gld x Mus spretus) F1 X C3H/HeJ-gld/gld] backcross mice we established a close linkage of the 202, 203, and 204 genes to the erythroid alpha-spectrin gene (Spna-1) on distal murine chromosome 1. Cosmids containing the 202, 203, and 204 genes were isolated from a library derived from AKR mouse DNA. Southern blot analysis of such cosmids revealed: (a) hybridization of a partial 203 cDNA to three genes of the 203 gene family; (b) cross-hybridization of the 202 and 204 genes with one another and with a third gene (designated as 201 gene), and (c) a close linkage of genes of the 203 family with the 201, 202, and 204 genes. These results indicate the existence of a cluster of at least six closely linked, interferon-activatable genes on distal murine chromosome 1 in the vicinity of the Spna-1 locus and also of the Minor lymphocyte stimulating locus (Mlsa).     

A linkage disequilibrium between genes at the serine protease inhibitor gene cluster on chromosome 14q32.1 is associated with Wegener's granulomatosis

The frequency of carriers of the alpha1-antitrypsin (alpha1-AT) deficiency allele PI*Z is increased in patients with Wegener's granulomatosis (WG). The polymorphic protease inhibitor (PI) gene is part of a cluster of serine protease inhibitor (serpin) genes (AACT; alpha1-antichymotrypsin, PCI; protein C inhibitor, CBG; corticosteroid binding globulin, PIL; PI-like pseudogene) at chromosome 14q32.1. In this study we investigated whether the serpin gene cluster contributes to the background of Wegener's granulomatosis. Therefore, phenotyping of alpha1-AT was performed and simple tandem repeat polymorphisms (STRP) in the genes for CBG, PI, and PCI as well as two STRP (D14S55 and D14S48) flanking the centromeric and one (D14S51) flanking the telomeric region of the gene cluster were examined in a population of 79 patients with WG and 128 unrelated healthy controls. In WG patients an increased frequency of the PI*Z defective allele is demonstrated as well as a linkage disequilibrium between all members of this gene cluster plus the centromeric and telomeric STRP. These results indicate an involvement of the serpin genes in the pathogenesis of Wegener's granulomatosis and it is possible that other genes located in the vicinity of D14S55 or D14S51 contribute to the genetic background of the disease.     

Combined sib-TDT and TDT provide evidence for linkage of the interleukin-1 gene cluster to erosive rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common disease of unknown aetiology which usually causes progressive destruction of the joints. Familial aggregation, twin studies and segregation analyses suggest that there is a genetic component to RA and the HLA-DRB1 locus in the major histocompatibility complex on chromosome 6 has been shown to be linked to, and associated with, RA susceptibility. It is likely that other genes with weaker effects are also involved, which may be difficult to detect using conventional parametric and non-parametric linkage methods. We have implemented the combined sib-TDT and TDT, in addition to parametric and non-parametric linkage methods, to investigate the candidate genes of the interleukin-1 (IL-1) gene cluster on chromosome region 2q13, since IL-1 is an important cytokine in the control of the inflammatory response that is central to RA pathology. Several tightly linked IL-1 cluster markers yielded suggestive evidence for linkage in the combined TDT in those families in which affected siblings did not share two HLA-DRB1 alleles identical by descent. The evidence was significant in those with severe disease, as assessed by the presence of bone erosions. In contrast, there was no evidence of linkage using non-parametric linkage analysis, but parametric analysis revealed weak evidence of linkage when marker-trait disequilibrium was incorporated into the analysis. The data provide preliminary evidence for linkage of genes of the IL-1 cluster to RA and suggest a possible role for this region in severe erosive disease.     

C-reactive protein levels and common polymorphisms of the interleukin-1 gene cluster and interleukin-6 gene in patients with coronary heart disease.

C-reactive protein (CRP) is an inflammatory marker associated with increased cardiovascular risk. Production of CRP is regulated by interleukin (IL)-1beta, IL-1 receptor antagonist and IL-6. In 160 patients with coronary heart disease (CHD) confirmed by angiography, we examined the relationship between CRP level and five polymorphisms in genes coding for these cytokines: IL-1B(-511), IL-1B(+3954), a variable number tandem repeat (VNTR) polymorphism in intron 2 of IL-1RN [IL-1RN(VNTR)], IL-6(-174) and IL-6(-572). CRP values were logarithmically normalized (log-CRP) for statistical calculations. In univariate analysis, carrier status for the IL-1B(+3954)T allele and IL-1RN(VNTR) allele 2 [IL-1RN(VNTR)*2] correlated with higher (P < 0.01) and lower (P < 0.05) log-CRP values, respectively. Among the potential confounding factors analysed, smoking, body mass index, total cholesterol (P < 0.05 for all) and diabetes (P = 0.056) were positively correlated with CRP level. After adjustment for non-genetic covariates, CRP levels remained significantly (P < 0.01) higher in carriers of IL-1B(+3954)T than in non-carriers: mean log-CRP (with 95% confidence interval) was 0.443 (0.311-0.574) for CT or TT genotypes compared with 0.240 (0.107-0.373) for the CC genotype, which corresponded to back-transformed CRP levels of 2.77 and 1.74 mg l(-1), respectively. Adjusted association was also significant for IL-1RN(VNTR)*2 (P < 0.01), with lower CRP levels in the presence of allele 2: the mean log-CRP value was 0.252 (0.115-0.388) for carriers and 0.421 (0.290-0.552) for non-carriers (CRP 1.79 and 2.64 mg l(-1), respectively). When alleles of both polymorphisms were entered into the model simultaneously, the association remained significant for IL-1B(+3954)T (P < 0.05), but not for IL-1RN(VNTR)*2. We conclude that IL-1B(+3954)T is associated with higher CRP levels in patients with CHD, and we found that this association was significant after adjustment for major risk factors. Our data also suggest a possible relationship of IL-1RN(VNTR)*2 with lower CRP levels in the same patients.     

Localization of the EPM1 gene for progressive myoclonus epilepsy on chromosome 21: linkage disequilibrium allows high resolution mapping

The gene for Progressive myoclonus epilepsy of Unverricht- Lundborgtype (EPM1) has previously been mapped by linkage to markerson chromosome 21q22.3. By analyzing crossover events in multiplexdisease families with newly detected markers from the regionwe were able to narrow the localization of EPM1 to an intervalof approximately 7 cM, between locl D21S212 and CD18. To furtherrefine the localization of the EPM1 gene we applied linkagedisequilibrium mapping In 38 Finnish families, consisting of12 with multiple affected children and 26 with a single affectedchild. Based on existing knowledge about the structure and historyof the Isolated Finnish population, we estimated genetic distancesbased on strong linkage disequilibrium to several marker lociand found that EPM1 resides within 0.3 cM or less of loci PFKL,D21S25 and D21S154. As this genetic distance translates intoa likely physical distance of 300 kb or less, these data providea basis for highly focused attempts to clone EPM1.     

Type A behavior and physiologic coronary risk factors in children of the family heart study: results from a 1-year follow-up

Although Type A behavior is recognized as an independent risk factor for coronary heart disease, little is known about its antecedents. The present study investigated relationships of Type A behavior as assessed by the Hunter-Wolf rating scale to physiologic coronary risk factors in children ranging from 8 to 15 years of age. In addition, gender differences and the stability of Type A behavior and physiologic risk factors were examined. Consistent with data based on adult samples, Type A behavior was generally unrelated to physiologic coronary risk factors and appears to be as stable as the other risk factors. There were no gender differences in either Type A behavior or other coronary risk factors.