Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder.
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Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized by multiple clinical features that include pigmentary retinal dystrophy, polydactyly, obesity, developmental delay, and renal defects. BBS is considered an autosomal recessive disorder, and recent positional cloning efforts have identified two BBS genes (BBS2 and BBS6). We screened our cohort of 163 BBS families for mutations in both BBS2 and BBS6 and report the presence of three mutant alleles in affected individuals in four pedigrees. In addition, we detected unaffected individuals in two pedigrees who carry two BBS2 mutations but not a BBS6 mutation. We therefore propose that BBS may not be a single-gene recessive disease but a complex trait requiring three mutant alleles to manifest the phenotype. This triallelic model of disease transmission may be important in the study of both Mendelian and multifactorial disorders. (+info)
Exploring the molecular basis of Bardet-Biedl syndrome.
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Few autosomal recessive disorders display the degree of pleiotropism and genetic heterogeneity found in Bardet-Biedl syndrome (BBS), a genetic disorder characterized primarily by retinal dystrophy, obesity, polydactyly, cognitive impairment and gonadal and renal dysgenesis. This relatively rare condition has been reported frequently, but we have only recently begun to appreciate the genetic complexities that give rise to this constellation of clinical findings. During the last 12 months, the first three of at least six BBS genes have been identified, providing us for the first time with the ability to formulate hypotheses regarding the molecular etiology of the disorder. Here we review the key elements of the phenotype and discuss the significance of the discovery of the first three BBS genes on the effort to identify the cellular causes of this syndrome. (+info)
BBS4 is a minor contributor to Bardet-Biedl syndrome and may also participate in triallelic inheritance.
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Bardet-Biedl syndrome (BBS) is an uncommon multisystemic disorder characterized primarily by retinal dystrophy, obesity, polydactyly, and renal dysfunction. BBS has been modeled historically as an autosomal recessive trait, under which premise six independent BBS loci (BBS1-BBS6) have been mapped in the human genome. However, extended mutational analyses of BBS2 and BBS6, the first two BBS genes cloned, suggest that BBS exhibits a more complex pattern of inheritance, in which three mutations at two loci simultaneously are necessary and sufficient in some families to manifest the phenotype. We evaluated the spectrum of mutations in the recently identified BBS4 gene with a combination of haplotype analysis and mutation screening on a multiethnic cohort of 177 families. Consistent with predictions from previous genetic analyses, our data suggest that mutations in BBS4 contribute to BBS in <3% of affected families. Furthermore, integrated mutational data from all three currently cloned BBS genes raise the possibility that BBS4 may participate in triallelic inheritance with BBS2 and BBS1, but not the other known loci. Establishment of the loci pairing in triallelism is likely to be important for the elucidation of the functional relationships among the different BBS proteins. (+info)
Clinical and genetic epidemiology of inherited renal disease in Newfoundland.
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Clinical and genetic epidemiology of inherited renal disease in Newfoundland. Newfoundland's geography, settlement, and socioeconomic development have produced a population useful for the study of genetic diseases. This review examines the clinical and genetic epidemiologic studies of inherited renal diseases undertaken in this population in the past 15 years. Common founder effects and large families through each generation provided very extensive pedigrees with autosomal-dominant diseases, such as polycystic kidney disease (PKD) and von Hippel-Lindau disease. In the former disease the diagnostic utility of renal ultrasound was determined, as was the prognostic impact of genotype, the role of the renin-angiotensin system in the pre-hypertensive phase, the potential for somatic mutations of the PKD2 gene, or the combination of mutations in the PKD1 and PKD2 genes, in single cells to induce cysts, and the demonstration that human transheterozygotes of PKD1 and -2 are not embryonically lethal. The presence of multiple genetic isolates and the high coefficient of kinship have predisposed to autosomal recessive diseases such as Bardet-Biedl syndrome (BBS), autosomal-recessive PKD, primary hyperoxaluria, and dihydroxyadenine urolithiasis. We have reported the clinical manifestations and natural history of the BBS, with particular emphasis on the fact that renal abnormalities are cardinal manifestations of the disease, the presence of at least six different genotypes, the identity and function of the BBS6 gene, and the presence of three different BBS6 mutations. Because of its relatively homogenous origins and high coefficient of kinship, Newfoundland's population also may be useful for the study of complex diseases such as preeclampsia. Using unbiased ascertainment and strict diagnostic criteria, we have found a significant risk of preeclampsia and non-proteinuric gestational hypertension in sisters of probands with preeclampsia, particularly when probands are defined by severity of preeclampsia, an observation that supports a study to search for susceptibility genes. We conclude that collaborations between clinical epidemiologists and molecular geneticists, using the Newfoundland population, have provided important clinical and mechanistic insights into inherited renal diseases. (+info)
Human limb malformations; an approach to the molecular basis of development.
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Analysis of human inherited limb malformations and of mouse mutants copying individual human mutations team up to promote the understanding of vertebrate limb development as a model for molecular regulatory interactions in animals. The strength of the human genetic contribution lies in the increasingly complete information on the human genome, transcriptome and proteome, as well as in the wealth of individual mutations interfering with limb development available for study. Based on the strong fundament of the human genome project, mapping and identification of novel genes associated with limb defects extends considerably the range of candidates beyond the repertoire of developmental genes and pathways known from animals. Attempts to correlate genotype and phenotype uncover a very broad range of genetic heterogeneity, i.e. different genes underlying the same phenotype, or allelic heterogeneity between families, i.e. clinically distinct phenotypes associated with mutations affecting the same gene. Mechanisms other than simple Mendelian inheritance have to be taken into consideration. Phenotypic variability within families might be explained by different modifying genes or environmental influence, whereas asymmetry of limb defects within one patient may be caused by epigenetic factors, such as somatic mosaicism or X-inactivation, or by non-genetic factors. The intimate knowledge of the genes and events governing limb pattern formation in humans and animals will elucidate the regulatory interactions underlying normal and pathological development, homeostasis, and repair, and thus propose targets for preventive measures and novel approaches to therapeutic intervention in the new era of molecular medicine. (+info)
Evaluation of complex inheritance involving the most common Bardet-Biedl syndrome locus (BBS1).
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Bardet-Biedl syndrome (BBS) is a genetic disorder with the primary features of obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism. Patients with BBS are also at increased risk for diabetes mellitus, hypertension, and congenital heart disease. BBS is known to map to at least six loci: 11q13 (BBS1), 16q21 (BBS2), 3p13-p12 (BBS3), 15q22.3-q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6). Although these loci were all mapped on the basis of an autosomal recessive mode of inheritance, it has recently been suggested-on the basis of mutation analysis of the identified BBS2, BBS4, and BBS6 genes-that BBS displays a complex mode of inheritance in which, in some families, three mutations at two loci are necessary to manifest the disease phenotype. We recently identified BBS1, the gene most commonly involved in Bardet-Biedl syndrome. The identification of this gene allows for further evaluation of complex inheritance. In the present study we evaluate the involvement of the BBS1 gene in a cohort of 129 probands with BBS and report 10 novel BBS1 mutations. We demonstrate that a common BBS1 missense mutation accounts for approximately 80% of all BBS1 mutations and is found on a similar genetic background across populations. We show that the BBS1 gene is highly conserved between mice and humans. Finally, we demonstrate that BBS1 is inherited in an autosomal recessive manner and is rarely, if ever, involved in complex inheritance. (+info)
Identification of a novel Bardet-Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2.
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Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder, the primary features of which include obesity, retinal dystrophy, polydactyly, hypogenitalism, learning difficulties, and renal malformations. Conventional linkage and positional cloning have led to the mapping of six BBS loci in the human genome, four of which (BBS1, BBS2, BBS4, and BBS6) have been cloned. Despite these advances, the protein sequences of the known BBS genes have provided little or no insight into their function. To delineate functionally important regions in BBS2, we performed phylogenetic and genomic studies in which we used the human and zebrafish BBS2 peptide sequences to search dbEST and the translation of the draft human genome. We identified two novel genes that we initially named "BBS2L1" and "BBS2L2" and that exhibit modest similarity with two discrete, overlapping regions of BBS2. In the present study, we demonstrate that BBS2L1 mutations cause BBS, thereby defining a novel locus for this syndrome, BBS7, whereas BBS2L2 has been shown independently to be BBS1. The motif-based identification of a novel BBS locus has enabled us to define a potential functional domain that is present in three of the five known BBS proteins and, therefore, is likely to be important in the pathogenesis of this complex syndrome. (+info)
Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome.
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Bardet-Biedl syndrome is a genetically and clinically heterogeneous disorder caused by mutations in at least seven loci (BBS1-7), five of which are cloned (BBS1, BBS2, BBS4, BBS6, and BBS7). Genetic and mutational analyses have indicated that, in some families, a combination of three mutant alleles at two loci (triallelic inheritance) is necessary for pathogenesis. To date, four of the five known BBS loci have been implicated in this mode of oligogenic disease transmission. We present a comprehensive analysis of the spectrum, distribution, and involvement in non-Mendelian trait transmission of mutant alleles in BBS1, the most common BBS locus. Analyses of 259 independent families segregating a BBS phenotype indicate that BBS1 participates in complex inheritance and that, in different families, mutations in BBS1 can interact genetically with mutations at each of the other known BBS genes, as well as at unknown loci, to cause the phenotype. Consistent with this model, we identified homozygous M390R alleles, the most frequent BBS1 mutation, in asymptomatic individuals in two families. Moreover, our statistical analyses indicate that the prevalence of the M390R allele in the general population is consistent with an oligogenic rather than a recessive model of disease transmission. The distribution of BBS oligogenic alleles also indicates that all BBS loci might interact genetically with each other, but some genes, especially BBS2 and BBS6, are more likely to participate in triallelic inheritance, suggesting a variable ability of the BBS proteins to interact genetically with each other. (+info)