Absence of linkage between 5q markers and serum IgE levels in four large atopic families

Background Both genetic and environmental influences have been suggested to control the immunoglobulin (Ig)E response to allergens and, as a result, provide susceptibility to atopic disease. Two recent reports suggested that a major gene controlling basal IgE levels in humans was transmitted in a pattern consistent with autosomal recessive inheritance and was located on the long arm of chromosome 5 in the interleukin (IL)-4 gene complex. Objective The purpose of this report is to evaluate evidence for linkage of IgE with polymorphic genetic markers in the candidate region of 5q in four large pedigrees originally selected for studies of atopy. Method Four large, highly characterized pedigrees in which IgE levels had been determined and genotypes at markers in the 5q candidate region were evaluated using both lod score and sib pair methods of analysis. Results In these pedigrees, we reject close to moderate hnkage (up to 5 cM) of an IgE locus with markers on 5q. Conclusion The genetic aspects of IgE regulation and its role in atopy remain controversial. The data suggest that should major genes be involved in the inheritance of atopy susceptibility, they are likely to be multiple in number and likely to involve interaction with other (exogenous) environmental exposures.     

Association between high serum total IgE levels and D11S97 on chromosome 11q13 in Japanese subjects.

The genetic linkage of atopy to chromosome 11q13 through maternally derived alleles has been previously reported. Linkage analysis in Japanese families did not confirm the existence of a major gene for atopy at this locus under the model of autosomal dominant inheritance. However, we observed a significant association between serum total IgE levels and genetic markers at this locus both in 14 Japanese atopic families and in 120 unrelated Japanese subjects. We detected eight alleles at the D11S97 locus and eight alleles in the CA/GT repeat region in the fifth intron of the Fc epsilon RI beta gene. A significantly increased frequency of the D11S97/PstI 0.96 kb allele was observed in the chromosomes of the subjects with high serum total IgE levels both in the family study (p < 0.001) and in the population study (p < 0.05). However, multipoint linkage analysis again did not show any evidence for the existence of a major gene regulating atopy on chromosome 11q13 with location scores to -35 under the model of maternal inheritance. Evidence against linkage was confirmed by the non-parametric linkage analysis, using the affected pedigree member method. Also, there was no substitution of isoleucine for leucine in the fourth transmembrane domain of Fc epsilon RI beta (Leu181), which was reported to be responsible for a subset of atopy in the British population. Therefore, the association of serum total IgE levels with chromosome 11q13 indicates that a gene or genes at this locus may contribute to the expression of high IgE levels in the Japanese population as well as in the British population, but the heterogeneity of the genetic regulation of serum total IgE levels is evident between the two populations.     

Initial report of a genome search for the affective disorder predisposition gene in the old order Amish pedigrees: Chromosomes 1 and 11

Family data have suggested that some forms of major affective disorder are genetic. Certain of the Old Order Amish pedigrees have a familial form of the disease. In this report we present the results of genetic analyses under autosomal dominant mode of transmission with reduced pentrance and three different disease hierarchies. The pedigrees were genotyped with 28 markers from chromosome 1 and 23 markers from chromosomes 11. None of the markers result in a significantly positive lod score. © 1994 Wiley-Liss, Inc.     

Genetic analysis using DNA polymorphism of the linkage between chromosome 11q13 and atopy and bronchial hyperresponsiveness to methacholine.

Previous studies have suggested that there is a genetic predisposition for the development of asthma and atopy. A recent study has also demonstrated that there is a striking link between chromosome 11q and the IgE response underlying asthma and rhinitis. To assess the linkage between chromosome 11q (region D11S97) and atopy or bronchial hyperresponsiveness (BH), we have studied nine families of two and, in many instances, three generations with the index case having asthma and/or atopy. With variable number of tandem repeat analysis with the probe, p lambda-MS.51, we have been unable to confirm a significant link between region D11S97 of chromosome 11q and either atopy or BH to methacholine. We have demonstrated that atopy and BH produce similar log of odds scores with linkage analysis at each recombination fraction from 0.001 to 0.5 with both Hinf1 and Taq1 restriction digests and that the use of either a positive skin prick test or positive RAST as a definition of atopy does not significantly alter the log of odds score.     

Charcot-Marie-Tooth disease: molecular characterization of patients from Central and Southern Italy

The syndrome of peroneal muscular atrophy, or Charcot-Marie-Tooth (CMT), disease represents the most common inherited peripheral neuropathy, with a prevalence of about 1 per 2500. The disease is usually transmitted in an autosomal dominant fashion, although it can display all the mendelian patterns of inheritance. The chromosome 17-linked form (CMT1a) appears to be the most common form of the disease in all the ethnic groups studied so far, Italians included, and is due to a tandem duplication in 17p11.2. In order to study the distribution of CMT types and to establish a genotype-phenotype correlation in patients from Central and Southern Italy, we collected 19 CMT pedigrees diagnosed in the years 1992–1993. Simple tandem repeats (STR) polymorphism analysis with the marker RM11-GT and Southern blotting with the probes pVAW409R3 and pVAW412 were performed, demonstrating a high prevalence (about 60%) or 17p duplication in the families studied. No clinical or electrophysiological differences were noted between CMT1 patients with or without 17p duplication, respectively. Two families affected by CMT2 showed no evidence of rearrangement at the D17S122 locus. These data are consistent with the hypothesis of a different molecular basis for CMT2.     

Familial atopy in Australian pedigrees: adventitious linkage to chromosome 8 is not confirmed nor is there evidence of linkage to the high affinity IgE receptor

Atopy frequently displays autosomal dominant inheritance and recent studies have favoured genetic linkage between atopy and the human chromosome 11q13. We have studied 12 extended families with aggregation of atopy consistent with autosomal dominant inheritance. The families have been studied for linkage of asthma and atopy to loci on chromosome 8p following the observation that one family suggested preliminary evidence of linkage to an anonymous hypervariable locus cloned from a DNA fingerprint and mapped to 8pter-p22. Subsequent analysis shows this putative linkage to be adventitious as the remaining 11 families do not support linkage between atopy and 8p, We have analysed the same families for evidence of linkage of atopy to loci on 11q13. In these families there is no evidence of association between atopy and the 11q loci stronger than that expected by chance alone; furthermore there is no suggestion subpopulation of these families display linkage between atopy and the loci. In addition neither the 8p loci nor the 11q loci exhibit evidence of linkage to atopy by affected sib-pair analysis. This also conflicts with previously published data for 11q.     

Evidence of a long QT founder gene with varying phenotypic expression in South African families.

We report five South African families of northern European descent (pedigrees 161, 162, 163, 164, and 166) in whom Romano-Ward long QT syndrome (LQT) segregates. The disease mapped to a group of linked markers on chromosome 11p15.5, with maximum combined two point lod scores, all generated at theta = 0, of 15.43 for the D11S922, 10.51 for the D11S1318, and 14.29 for the tyrosine hydroxylase (TH) loci. Recent studies have shown that LQT is caused by an Ala212Val mutation in a potassium channel gene (KVLQT1) in pedigrees 161 to 164. We report that the same mutation is responsible for the disease in pedigree 166. Haplotype construction showed that all the families shared a common haplotype, suggesting a founder gene effect. DNA based identification of gene carriers allowed assessment of the clinical spectrum of LQT. The QTc interval was significantly shorter in both carriers and non-carriers in pedigree 161 (0.48 s and 0.39 s, respectively) than the same two groups in pedigree 161 (0.52 s and 0.42 s, respectively). The spectrum of clinical symptoms appeared more severe in pedigree 162. The possible influence of modulating genetic factors, such as HLA status and sex of family members, on the expression of an LQT founder gene is discussed.     

An autosomal dominant posterior polar cataract locus maps to human chromosome 20p12-q12

We assigned the locus for a previously reported new type of autosomal dominant posterior polar cataract (CPP3) to 20p12-q12 by a genome-wide two-point linkage analysis with microsatellite markers. CPP3 is characterized by progressive, disc-shaped, posterior subcapsular opacity. The disease was seen in 10 members of a Japanese family and transmitted in an autosomal dominant fashion through four generations. We obtained a maximum lod score (Zmax) of 3.61 with a recombination fraction (theta) of 0.00 for markers D20S917, D20S885 and D20S874. Haplotype analysis gave the disease gene localization at a 15.7-cM interval between D20S851 and D20S96 loci on chromosome 20p12-q12. Since the BFSP1 that encodes the lens-specific beaded filament structural protein 1 (filensin) has been mapped around the CPP3 region, we performed sequence analysis on its entire coding region. However, no base substitution or deletion was detected in the CPP3 patients. The mapping of the CPP3 locus to 20p12-q12 not only expands our understanding of the genetic heterogeneity in autosomal dominant posterior polar cataracts but also is a clue for the positional cloning of the disease gene.     

Autosomal dominant late-onset spinal motor neuronopathy is linked to a new locus on chromosome 22q11.2-q13.2

Spinal muscular atrophies (SMAs) are hereditary disorders characterized by degeneration of lower motor neurons. Different SMA types are clinically and genetically heterogeneous and many of them show significant phenotypic overlap. We recently described the clinical phenotype of a new disease in two Finnish families with a unique autosomal dominant late-onset lower motor neuronopathy. The studied families did not show linkage to any known locus of hereditary motor neuron disease and thus seemed to represent a new disease entity. For this study, we recruited two more family members and performed a more thorough genome-wide scan. We obtained significant linkage on chromosome 22q, maximum LOD score being 3.43 at marker D22S315. The linked area is defined by flanking markers D22S686 and D22S276, comprising 18.9 Mb. The region harbours 402 genes, none of which is previously known to be associated with SMAs. This study confirms that the disease in these two families is a genetically distinct entity and also provides evidence for a founder mutation segregating in both pedigrees.     

Genetic linkage of systemic lupus erythematosus with chromosome 11q14 (SLEH1) in African-American families stratified by a nucleolar antinuclear antibody pattern

Systemic lupus erythematosus (SLE) is an autoimmune disease with complex genetics. We evaluated pedigrees multiplex for SLE that had an affected with antinucleolar antibodies to increase the homogeneity for genetic linkage analysis. We found a significant linkage effect on chromosome 11q14 at marker D11S2002 in African-American Pedigrees. This effect produced a maximum LOD score of 5.62 using a dominant inheritance model with 95% penetrance in males and 99% penetrance in females. The results were supported by multipoint linkage analysis. Fine mapping of the region with two additional markers within 6 cM of D11S2002 further provided evidence of linkage in this region. Linkage at D11S2002, named SLEH1, was previously found in some of these same African-American pedigrees multiplex for SLE, but who were stratified by hemolytic anemia (Kelly et al, submitted). In conclusion, an important SLE susceptibility gene, SLEH1 at 11q14, is identified in African-Americans when stratifying pedigrees by antinucleolar autoantibodies.     

Fine mapping of a distinctive autosomal dominant vacuolar neuromyopathy using 11 novel microsatellite markers from chromosome band 19p13.3

We previously mapped a distinctive autosomal dominant vacuolar neuromyopathy on human chromosome 19p13 in an 8cM region, delimited by D19S209 and D19S177 markers. We now report the fine mapping of the disease locus within an interval of 250 Kb by haplotype analysis performed using a set of 11 novel microsatellite markers isolated from the candidate region.     

用与PKD2紧密连锁的微卫星DNA对2型常染色体显性多囊肾病进行基因诊断

目的　应用DKD2紧密连锁的微卫星DNA对 2型染色体显性多囊肾病进行基因诊断。方法应用聚合酶链反应 毛细管电泳 基因扫描方法对PKD2基因侧翼微卫星D4S15 3 4、D4S15 42、D4S15 63、D4S2 460和D4S42 3进行基因分型 ,对常染色体显性多囊肾病家系成员进行连锁分析 ,确定患病家系是否与PKD2连锁 ,并对未发病成员进行基因诊断。结果　通过连锁分析 2 0个家系 ,寻找到 3个与PKD2连锁的多囊肾病家系 ;在 3个家系的 4名未发病成员中发现 2例携带PKD2基因突变的症状前个体。结论　连锁分析是多囊肾病异质性研究和基因诊断的一种快速、简便的方法。     

A locus for autosomal dominant posterior polar cataract on chromosome 1p

Autosomal dominant congenital cataract is a clinically and genetically heterogeneous lens disease. Here we report the linkage of a locus for autosomal dominant posterior polar cataract (CPP) to the distal short arm of chromosome 1. To map the CPP locus we performed molecular genetic linkage analysis using microsatellite markers in a three- generation pedigree. After exclusion of 13 known loci and candidate lens genes for autosomal dominant cataract, we obtained significantly positive LOD scores for markers D1S508 (Z = 3.14, theta = 0) and D1S468 (Z = 2.71, theta = 0). Multipoint analysis gave a maximum LOD score of 3.48 (theta = 0.07) between markers D1S508 and D1S468. From haplotype data, however, CPP probably lies in the telomeric interval D1S2845- 1pter, which includes the locus for the clinically distinct Volkman congenital cataract (CCV). This study provides the first evidence for genetic heterogeneity of autosomal dominant posterior polar cataract for which a locus had been linked previously to chromosome 16q.      

Lack of linkage between atopy and locus 11q13

Atopy as defined in terms of IgE responsiveness was reported to be controlled by a single gene in British families, and this concept was further supported by a significant linkage between atopy and restriction fragment length polymorphism (RFLP) detected by a DNA probe specific to chromosome 11q13. To confirm this observation in a Japanese population, segregation and linkage analyses were done in four large families. Although segregation patterns of atopy were in agreement with the pattern of autosomal dominant inheritance, there was no significant linkage between atopy and locus 11q13. Alterations in the definitions of atopy did not affect the results. These findings suggested the presence of heterogeneity in genetic elements of atopy, even though atopy may be determined mainly by a single dominant gene.     

NRL S50T mutation and the importance of 'founder effects' in inherited retinal dystrophies

The aim of this work was to identify NRL mutations in a panel of 200 autosomal dominant retinitis pigmentosa (adRP) families. All samples were subjected to heteroduplex analysis of the three exons of the NRL gene, and HphI restriction digest analysis of exon 2 (to identify the S50T mutation). Families found to have the S50T mutation, and six additional larger pedigrees (which had previously been excluded from the other nine adRP loci) underwent linkage analysis using polymorphic markers located in the region of 14q11. HphI restriction analysis followed by direct sequencing of the amplified NRL exon 2 product demonstrated the presence of the NRL S50T sequence change in three adRP families. Comparison of marker haplotypes in affected individuals from these families with those of affected members of the original 14q11 linked family revealed a common disease haplotype for markers within the adRP locus. Recombination events observed in these families define an adRP critical interval of 14.9 cM between D13S72 and D14S1041. Linkage analysis enabled all six of the larger adRP pedigrees to be excluded from the 14q11 locus. The NRL S50T mutation represents another example of a 'founder effect' in a dominantly inherited retinal dystrophy. Identification of such 'founder effects' may greatly simplify diagnostic genetic screening and lead to better prognostic counselling. The exclusion of several adRP families from all ten adRP loci indicates that at least one further adRP locus remains to be found.     

A locus for autosomal dominant anterior polar cataract on chromosome 17p

Inherited cataract is a clinically and genetically heterogeneous disease. Here we report the identification of a new locus for an autosomal dominant anterior polar cataract on the short arm of chromosome 17. To map this new locus we performed genetic linkage analysis with microsatellite markers in a four-generation pedigree. After exclusion of seven candidate loci for cataract, we obtained significant positive LOD scores for markers D17S849 (Z = 4.01 / theta = 0.05) and D17S796 (Z = 4.17 / theta = 0.05). Multipoint analysis gave a maximum LOD score of 5.2 (theta max = 0.06) between these two markers. From haplotype analysis, the cataract locus lies in the 13 cM interval between markers D17S849 and D17S796. This study provides the first genetic mapping of an autosomal dominant anterior polar cataract.      

Genetic inheritance of susceptibility to tinea imbricata.

Segregation analysis on 228 family pedigrees collected from a Papua New Guinean population provided data that strongly supported a previous report of an autosomal recessive pattern of inheritance of a susceptibility to tinea imbricata. The frequency of the susceptibility gene within the population studied was found to be 0.49 +/- 0.04, calculated on the assumption of an autosomal recessive mode of inheritance. However, in spite of the strong evidence in support of autosomal recessive inheritance, the possibility of autosomal dominant inheritance with reduced penetrance cannot be excluded.     

Linkage between severe atopy and chromosome 11q13 in Japanese families

Atopy, characterised by allergic asthma and rhinitis, is due to increased IgE responses to common aeroallergens. An Oxford group has described maternal inheritance of atopy, where there is significant linkage between IgE responsiveness and a VNTR marker D11S97 and a CA microsatellite within a candidate gene, the high affinity IgE receptor β subunit(FcεRIβ), on chromosome 11q. Attempts at independent replication have produced conflicting results. We therefore recruited 270 atopic asthmatic probands in a Japanese community population for genetic linkage analysis. Four families, each with more than 15 meioses and a clear phenotype for atopy, were selected for genetic analysis. Atopy was defined as presence of all of raised total IgE, positive RAST and skin tests to three or more aeroallergens; non-atopy, as absence of all these criteria. Linkage analysis showed a maximum two-point lod score of 9.35 for D11S97 and FcεRIβ under the assumption of unequal rates of maternal and paternal recombination. Two families showed close genetic linkage with FcεRIβ with a pattern of maternal inheritance. These results from a Japanese population provide further evidence for genetic linkage between severe atopy and chromosome 11q13 and the likelihood of genomic imprinting at the locus.     

Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11

Hereditary multiple exostoses (EXT) is an autosomal dominantdisorder of enchondral bone formation characterized by multiplebony outgrowths (exostoses), with progression to osteosarcomain a minority of cases. The exclusive involvement of skeletalabnormalities distinguishes EXT from the clinically more complexLanger – Giedion syndrome (LGS), which is associated withdeletions at chromosome 8q24. Previously, linkage analysis hasrevealed a locus for EXT in the LGS region on chromosome 8q24.However, locus heterogeneity was apparent with 30% of the familiesbeing unlinked to 8q24. We report on two large pedigrees segregatingEXT in which linkage to the LGS region was excluded. To localizethe EXT gene(s) in these families we performed a genome searchincluding 254 microsatellite markers dispersed over all autosomesand the X chromosome. In both families evidence was obtainedfor linkage to markers from the proximal short and long armsof chromosome 11. Two-point analysis gave the highest lod scorefor D11S554 (Z_max = 7.148 at theta = 0.03). Multipoint analysisindicated a map position for the EXT gene between D11S905 andD11S916, with a peak multipoint lod score of 8. 10 at 6 cM fromD11S935. The assignment of a second locus for EXT to the pericentromericregion of chromosome 11 implicates an area that is particularlyrich in genes responsible for developmental abnormalities andneoplasia.     

Common pathogenetic mechanism involving human chromosome 18 in familial and sporadic ileal carcinoid tumors

Serotonin producing endocrine carcinoma of small intestine (ileal carcinoid) is a clinically distinct endocrine tumor. It is generally considered as a sporadic disease and its molecular etiology is poorly understood. We report comprehensive clinical and molecular studies of 55 sporadic and familial patients diagnosed with this condition. Nine pedigrees encompassing 23 affected subjects were established, consistent with autosomal dominant mode of inheritance. Familial and sporadic patients demonstrated indistinguishable clinical pictures. Molecular analyses of 61 tumors from 45 individuals, including eight familial and 37 sporadic patients, aimed at determination of global copy number aberrations using BAC and Illumina SNP arrays and gene expression profiling by Affymetrix chips. Chromosome 18 aberrations were identified in both sporadic and in familial tumors; 100% vs. 38%, respectively. Other, less frequent aberrations were also common for both groups. Global expression profiles revealed no differentially expressed genes. Frequent gain of chromosome 7 was exclusively observed in metastases, when patient matched primary tumors and metastases were compared. Notably, the latter aberration correlated with solid growth pattern morphology (P < 0.01), a histopathological feature that has previously been related to worse prognosis. The clinical and molecular similarities identified between sporadic and familial cases suggest a common pathogenetic mechanism involved in tumor initiation. The familial variant of ileal carcinoid represents a previously unrecognized autosomal dominant inherited tumor disease, which we propose to call Familial Ileal Endocrine Carcinoma (FIEC). Our findings indicate the location of a FIEC tumor suppressor gene near the telomere of 18q, involved in development of inherited and sporadic tumors.