Evidence that mutations in the X-linked DDP gene cause incompletely penetrant and variable skewed X inactivation.
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X chromosome inactivation results in the random transcriptional silencing of one of the two X chromosomes early in female development. After random inactivation, certain deleterious X-linked mutations can create a selective disadvantage for cells in which the mutation is on the active X chromosome, leading to X inactivation patterns with the mutation on the inactive X chromosome in nearly 100% of the individual's cells. In contrast to the homogeneous patterns of complete skewed inactivation noted for many X-linked disorders, here we describe a family segregating a mutation in the dystonia-deafness peptide (DDP) gene, in which female carriers show incompletely penetrant and variable X inactivation patterns in peripheral blood leukocytes, ranging between 50:50 and >95:5. To address the genetic basis for the unusual pattern of skewing in this family, we first mapped the locus responsible for the variable skewing to the proximal long arm (Xq12-q22) of the X chromosome (Z=5. 7, P=.002, LOD score 3.57), a region that includes both the DDP and the XIST genes. Examination of multiple cell types from women carrying a DDP mutation and of peripheral blood leukocytes from women from two unrelated families who carry different mutations in the DDP gene suggests that the skewed X inactivation is the result of selection against cells containing the mutant DDP gene on the active X chromosome, although skewing is apparently not as severe as that seen for many other deleterious X-linked mutations. Thus, DDP is an example of an X-linked gene for which mutations cause partial cell selection and thus incompletely skewed X inactivation in peripheral blood leukocytes. (+info)
Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36.
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Combining data from a genomic screen in 70 families with a high risk for prostate cancer (PC) with data from candidate-region mapping in these families and an additional 71 families, we have localized a potential hereditary PC-susceptibility locus to chromosome 1p36. Because an excess of cases of primary brain cancer (BC) have been observed in some studies of families with a high risk for PC, and because loss of heterozygosity at 1p36 is frequently observed in BC, we further evaluated 12 families with both a history of PC and a blood relative with primary BC. The overall LOD score in these 12 families was 3.22 at a recombination fraction (theta) of .06, with marker D1S507. On the basis of an a priori hypothesis, this group was stratified by age at diagnosis of PC. In the younger age group (mean age at diagnosis <66 years), a maximum two-point LOD score of 3.65 at straight theta = .0 was observed, with D1S407. This linkage was rejected in both early- and late-onset families without a history of BC (LOD scores -7.12 and -6.03, respectively, at straight theta = .0). After exclusion of 3 of the 12 families that had better evidence of linkage to previously described PC-susceptibility loci, linkage to the 1p36 region was suggested by a two-point LOD score of 4.74 at straight theta = .0, with marker D1S407. We conclude that a significant proportion of these families with both a high risk for PC and a family member with BC show linkage to the 1p36 region. (+info)
Analysis of affected sib pairs, with covariates--with and without constraints.
(3/637)
Covariate models have previously been developed as an extension to affected-sib-pair methods in which the covariate effects are jointly estimated with the degree of excess allele sharing. These models can estimate the differences in sib-pair allele sharing that are associated with measurable environment or genes. When there are no covariates, the pattern of identical-by-descent allele sharing in affected sib pairs is expected to fall within a small triangular region of the potential parameter space, under most genetic models. By restriction of the estimated allele sharing to this triangle, improved power is obtained in tests for genetic linkage. When the affected-sib-pair model is generalized to allow for covariates that affect allele sharing, however, new constraints and new methods for the application of constraints are required. Three generalized constraint methods are proposed and evaluated by use of simulated data. The results compare the power of the different methods, with and without covariates, for a single-gene model with age-dependent onset and for quantitative and qualitative gene-environment and gene-gene interaction models. Covariates can improve the power to detect linkage and can be particularly valuable when there are qualitative gene-environment interactions. In most situations, the best strategy is to assume that there is no dominance variance and to obtain constrained estimates for covariate models under this assumption. (+info)
Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction.
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The Smads are a family of nine related proteins which function as signaling intermediates for the transforming growth factor beta (TGF-beta) superfamily of ligands. To discern the in vivo functions of one of these Smads, Smad3, we generated mice harboring a targeted disruption of this gene. Smad3 null mice, although smaller than wild-type littermates, are viable, survive to adulthood, and exhibit an early phenotype of forelimb malformation. To study the cellular functions of Smad3, we generated Smad3 null mouse embryonic fibroblasts (MEFs) and dermal fibroblasts. We demonstrate that null MEFs have lost the ability to form Smad-containing DNA binding complexes and are unable to induce transcription from the TGF-beta-responsive promoter construct, p3TP-lux. Using the primary dermal fibroblasts, we also demonstrate that Smad3 is integral for induction of endogenous plasminogen activator inhibitor 1. We subsequently demonstrate that Smad3 null MEFs are partially resistant to TGF-beta's antiproliferative effect, thus firmly establishing a role for Smad3 in TGF-beta-mediated growth inhibition. We next examined cells in which Smad3 is most highly expressed, specifically cells of immune origin. Although no specific developmental defect was detected in the immune system of the Smad3 null mice, a functional defect was observed in the ability of TGF-beta to inhibit the proliferation of splenocytes activated by specific stimuli. In addition, primary splenocytes display defects in TGF-beta-mediated repression of cytokine production. These data, taken together, establish a role for Smad3 in mediating the antiproliferative effects of TGF-beta and implicate Smad3 as a potential effector for TGF-beta in modulating immune system function. (+info)
Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population.
(5/637)
Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever with serositis or synovitis. The FMF gene (MEFV) was cloned recently, and four missense mutations were identified. Here we present data from non-Ashkenazi Jewish and Arab patients in whom we had not originally found mutations and from a new, more ethnically diverse panel. Among 90 symptomatic mutation-positive individuals, 11 mutations accounted for 79% of carrier chromosomes. Of the two mutations that are novel, one alters the same residue (680) as a previously known mutation, and the other (P369S) is located in exon 3. Consistent with another recent report, the E148Q mutation was observed in patients of several ethnicities and on multiple microsatellite haplotypes, but haplotype data indicate an ancestral relationships between non-Jewish Italian and Ashkenazi Jewish patients with FMF and other affected populations. Among approximately 200 anonymous Ashkenazi Jewish DNA samples, the MEFV carrier frequency was 21%, with E148Q the most common mutation. Several lines of evidence indicate reduced penetrance among Ashkenazi Jews, especially for E148Q, P369S, and K695R. Nevertheless, E148Q helps account for recessive inheritance in an Ashkenazi family previously reported as an unusual case of dominantly inherited FMF. The presence of three frequent MEFV mutations in multiple Mediterranean populations strongly suggests a heterozygote advantage in this geographic region. (+info)
Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance.
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Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance. Most patients have a heterozygous mutation in the APT1 gene, which encodes Fas (CD95, APO-1), mediator of an apoptotic pathway crucial to lymphocyte homeostasis. Of 17 unique APT1 mutations in unrelated ALPS probands, 12 (71%) occurred in exons 7-9, which encode the intracellular portion of Fas. In vitro, activated lymphocytes from all 17 patients showed apoptotic defects when exposed to an anti-Fas agonist monoclonal antibody. Similar defects were found in a Fas-negative cell line transfected with cDNAs bearing each of the mutations. In cotransfection experiments, Fas constructs with either intra- or extracellular mutations caused dominant inhibition of apoptosis mediated by wild-type Fas. Two missense Fas variants, not restricted to patients with ALPS, were identified. Variant A(-1)T at the Fas signal-sequence cleavage site, which mediates apoptosis less well than wild-type Fas and is partially inhibitory, was present in 13% of African American alleles. Among the ALPS-associated Fas mutants, dominant inhibition of apoptosis was much more pronounced in mutants affecting the intracellular, versus extracellular, portion of the Fas receptor. Mutations causing disruption of the intracellular Fas death domain also showed a higher penetrance of ALPS phenotype features in mutation-bearing relatives. Significant ALPS-related morbidity occurred in 44% of relatives with intracellular mutations, versus 0% of relatives with extracellular mutations. Thus, the location of mutations within APT1 strongly influences the development and the severity of ALPS. (+info)
Genetic linkage of IgA deficiency to the major histocompatibility complex: evidence for allele segregation distortion, parent-of-origin penetrance differences, and the role of anti-IgA antibodies in disease predisposition.
(7/637)
Immunoglobulin A (IgA) deficiency (IgAD) is characterized by a defect of terminal lymphocyte differentiation, leading to a lack of IgA in serum and mucosal secretions. Familial clustering, variable population prevalence in different ethnic groups, and a predominant inheritance pattern suggest a strong genetic predisposition to IgAD. The genetic susceptibility to IgAD is shared with a less prevalent, but more profound, defect called "common variable immunodeficiency" (CVID). Here we show an increased allele sharing at 6p21 in affected members of 83 multiplex IgAD/CVID pedigrees and demonstrate, using transmission/diseqilibrium tests, family-based associations indicating the presence of a predisposing locus, designated "IGAD1," in the proximal part of the major histocompatibility complex (MHC). The recurrence risk of IgAD was found to depend on the sex of parents transmitting the defect: affected mothers were more likely to produce offspring with IgAD than were affected fathers. Carrier mothers but not carrier fathers transmitted IGAD1 alleles more frequently to the affected offspring than would be expected under random segregation. The differential parent-of-origin penetrance is proposed to reflect a maternal effect mediated by the production of anti-IgA antibodies tentatively linked to IGAD1. This is supported by higher frequency of anti-IgA-positive females transmitting the disorder to children, in comparison with female IgAD nontransmitters, and by linkage data in the former group. Such pathogenic mechanisms may be shared by other MHC-linked complex traits associated with the production of specific autoantibodies, parental effects, and a particular MHC haplotype. (+info)
Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans.
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Since little is known about chromosomal locations harboring type 2 diabetes-susceptibility genes, we conducted a genomewide scan for such genes in a Mexican American population. We used data from 27 low-income extended Mexican American pedigrees consisting of 440 individuals for whom genotypic data are available for 379 markers. We used a variance-components technique to conduct multipoint linkage analyses for two phenotypes: type 2 diabetes (a discrete trait) and age at onset of diabetes (a truncated quantitative trait). For the multipoint analyses, a subset of 295 markers was selected on the basis of optimal spacing and informativeness. We found significant evidence that a susceptibility locus near the marker D10S587 on chromosome 10q influences age at onset of diabetes (LOD score 3.75) and is also linked with type 2 diabetes itself (LOD score 2.88). This susceptibility locus explains 63.8%+/-9.9% (P=. 000016) of the total phenotypic variation in age at onset of diabetes and 65.7%+/-10.9% (P=.000135) of the total variation in liability to type 2 diabetes. Weaker evidence was found for linkage of diabetes and of age at onset to regions on chromosomes 3p, 4q, and 9p. In conclusion, our strongest evidence for linkage to both age at onset of diabetes and type 2 diabetes itself in the Mexican American population was for a region on chromosome 10q. (+info)