Bardet–Biedl syndrome 1 genotype and obesity in the Newfoundland population

Fan, Yanli; Rahman, Proton; Peddle, Lynette; Hefferton, Donna; Gladney, Neil; Moore, Susan; Green, J S; Parfrey, Patrick S.; Davidson, William S.

doi:10.1038/sj.ijo.0802601

Cited by 26 publications

(23 citation statements)

References 34 publications

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“…The reported variation in the contribution of certain BBS genes, in particular BBS1, which accounts for only 20-30% of cases in Caucasians [27], suggests that other BBS genes remain to be identified. Interestingly, with regard to the obesity phenotype, the frequency of the most common BBS mutation, M390R, is identical among obese and non-obese individuals in a Newfoundland population, indicating that BBS mutations are unlikely to function in the pathogenesis of nonsyndromic obesity [34]. Consistent with these findings, Anderson and colleagues [35] found that BBS6 mutations are not linked to obesity in a Danish population with juvenile onset obesity.…”

Section: Gene Identificationmentioning

confidence: 80%

Bardet-Biedl syndrome: an emerging pathomechanism of intracellular transport

Blacque

Leroux

2006

Cell. Mol. Life Sci.

171

136

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From a handful of uncloned genetic loci 6 years ago, great strides have been made in understanding the genetic and molecular aetiology of Bardet-Biedl syndrome (BBS), a rare pleiotropic disorder characterised by a multitude of symptoms, including obesity, retinal degeneration and cystic kidneys. Presently, 11 BBS genes have been cloned, with the likelihood that yet more BBS genes remain undiscovered. In 2003, a major breakthrough was made when it was shown that BBS is likely caused by defects in basal bodies and/or primary cilia. Since then, studies in numerous animal models of BBS have corroborated the initial findings and, in addition, have further refined the specific functions of BBS proteins. These include roles in establishing planar cell polarity (noncanonical Wnt signaling) in mice and zebrafish, modulating intraflagellar transport and lipid homeostasis in worms, and regulating intracellular trafficking and centrosomal functions in zebrafish and human tissue culture cells. From these discoveries, a common theme has emerged, namely that the primary function of BBS proteins may be to mediate and regulate microtubule-based intracellular transport processes.

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Section: Gene Identificationmentioning

confidence: 80%

Bardet-Biedl syndrome: an emerging pathomechanism of intracellular transport

Blacque

Leroux

2006

Cell. Mol. Life Sci.

171

136

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“…Only two association studies of the BBS1 common mutation (M390R) and of missense SNPs in BBS6 have been performed in relation to obesity, which suggested that heterozygosity for the tested variants does not contribute significantly to the risk of obesity in the population (with the possible exception of the rare BBS6 variant A242S). 44,45 The cumulative prevalence of BBS mutation carriers indicates that the finding of a third mutated allele can occur by chance in 2% of BBS patients (or 1.5% in the present state of incomplete identification of BBS genes).…”

Section: Discussionmentioning

confidence: 99%

Pitfalls of homozygosity mapping: an extended consanguineous Bardet–Biedl syndrome family with two mutant genes (BBS2, BBS10), three mutations, but no triallelism

et al. 2006

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The extensive genetic heterogeneity of Bardet-Biedl syndrome (BBS) is documented by the identification, by classical linkage analysis complemented recently by comparative genomic approaches, of nine genes (BBS1-9) that account cumulatively for about 50% of patients. The BBS genes appear implicated in cilia and basal body assembly or function. In order to find new BBS genes, we performed SNP homozygosity mapping analysis in an extended consanguineous family living in a small Lebanese village. This uncovered an unexpectedly complex pattern of mutations, and led us to identify a novel BBS gene (BBS10). In one sibship of the pedigree, a BBS2 homozygous mutation was identified, while in three other sibships, a homozygous missense mutation was identified in a gene encoding a vertebrate-specific chaperonine-like protein (BBS10). The single patient in the last sibship was a compound heterozygote for the above BBS10 mutation and another one in the same gene. Although triallelism (three deleterious alleles in the same patient) has been described in some BBS families, we have to date no evidence that this is the case in the present family. The analysis of this family challenged linkage analysis based on the expectation of a single locus and mutation. The very high informativeness of SNP arrays was instrumental in elucidating this case, which illustrates possible pitfalls of homozygosity mapping in extended families, and that can be explained by the rather high prevalence of heterozygous carriers of BBS mutations (estimated at one in 50 in Europeans).

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“…Clinical presentations of the patients from families NF-B7, NF-B8, NF-B10, NF-B12, NF-B15, and NF-B19 have been described (Green et al 1989;O'Dea et al 1996) and NF-B23 will be described elsewhere (Moore et al, submitted). The characteristics of volunteers from the Newfoundland populations who acted as controls or who were identified as carrying a BBS1 mutation are described in Fan et al (2004b). Informed consent was obtained from the subjects and this study was approved by the Human Investigation Committee of Memorial University and the Research Ethics Board at Simon Fraser University.…”

Section: Subjectsmentioning

confidence: 99%

“…A mutational screen of the exons and exon-intron boundaries of BBS1 was performed by direct sequence analysis of PCR amplified products (Fan et al 2004b). Primers and conditions are available upon request from Y.…”

Section: Subjectsmentioning

confidence: 99%

“…Four hundred apparently unrelated volunteers from the south-west corner of Newfoundland were screened for the M390R mutation. Six individuals were identified as heterozygous carriers of this mutation indicating that the frequency of the M390R allele is 0.0075 in this region of Newfoundland (Fan et al 2004b). …”

Section: Identification Of a Common Mutation In Newfoundland Bbs1 Fammentioning

confidence: 99%

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Linkage disequilibrium mapping in the Newfoundland population: a re-evaluation of the refinement of the Bardet?Biedl syndrome 1 critical interval

et al. 2004

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Genetically isolated populations, such as Newfoundland, have contributed greatly to the identification of disease-causing genes. A linkage disequilibrium (LD) study involving six Newfoundland families predicted a critical interval for Bardet-Biedl syndrome 1 (BBS1) (Young et al. in Am J Hum Genet 65:1680-1687, 1999), but the subsequent identification of BBS1 revealed that it lies outside this region. This suggested that either there is another gene responsible for BBS in these families or the Newfoundland population may not be ideal for LD studies. We screened these six Newfoundland families for mutations in BBS1 and found that affected individuals in five of them were homozygous for the same M390R mutation. There was no evidence for any BBS1 mutation in the affected individual in the sixth family. Therefore, one of the criteria for LD mapping was not met; namely, there should be a single disease-causing allele in the population. Haplotype analysis of unaffected individuals from south-west Newfoundland and English BBS1 patients homozygous for M390R, revealed that a second criterion for LD mapping was violated. The M390R mutation occurred in a common haplotype and both of these chromosomes, the ancestral wild-type and disease-causing haplotypes, were introduced to Newfoundland and spread by a founder effect. Moreover, it was found that disease-associated alleles occurred at relatively high frequencies in normal haplotypes and this probably accounted for the incorrect prediction in the previous LD study. Knowing the amount of genetic variation and its distribution in the Newfoundland population would be useful to maximize its potential for mapping hereditary disorders.

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Bardet–Biedl syndrome 1 genotype and obesity in the Newfoundland population

Cited by 26 publications

References 34 publications

Bardet-Biedl syndrome: an emerging pathomechanism of intracellular transport

Bardet-Biedl syndrome: an emerging pathomechanism of intracellular transport

Pitfalls of homozygosity mapping: an extended consanguineous Bardet–Biedl syndrome family with two mutant genes (BBS2, BBS10), three mutations, but no triallelism

Linkage disequilibrium mapping in the Newfoundland population: a re-evaluation of the refinement of the Bardet?Biedl syndrome 1 critical interval

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