Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy

Zaghloul, Norann A.; Katsanis, Nicholas

doi:10.1172/jci37041

Cited by 334 publications

(321 citation statements)

References 124 publications

(147 reference statements)

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“…We have shown previously that suppression of some BBS proteins in zebrafish causes gastrulation defects that include shortened body axes, longer somites, and broad and kinked notochords (14,16,17,20,21). These phenotypes are consistent with abnormal planar cell polarity (PCP) signaling (21,22,24,25), which likely underlies several clinical phenotypes in patients who have BBS, including hearing defects (20), neural tube closure abnormalities (26), renal cyst formation (27), and possibly obesity and cognitive impairment (28). The fact that these observations are likely relevant to the etiopathology of BBS (20,21,(23)(24)(25), and true for all seven bbs orthologues tested (bbs1, bbs4, bbs6, bbs10, bbs12, mks1, and cep290) as well for as the three BBS modifiers mgc1203, mks3, and rpgrip1l, suggested that they might represent useful assays for all BBS genes.…”

Section: Resultsmentioning

confidence: 87%

Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet–Biedl syndrome

Zaghloul

Liu

Gerdes

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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109

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Technological advances hold the promise of rapidly catalyzing the discovery of pathogenic variants for genetic disease. However, this possibility is tempered by limitations in interpreting the functional consequences of genetic variation at candidate loci. Here, we present a systematic approach, grounded on physiologically relevant assays, to evaluate the mutational content (125 alleles) of the 14 genes associated with Bardet-Biedl syndrome (BBS). A combination of in vivo assays with subsequent in vitro validation suggests that a significant fraction of BBS-associated mutations have a dominantnegative mode of action. Moreover, we find that a subset of common alleles, previously considered to be benign, are, in fact, detrimental to protein function and can interact with strong rare alleles to modulate disease presentation. These data represent a comprehensive evaluation of genetic load in a multilocus disease. Importantly, superimposition of these results to human genetics data suggests a previously underappreciated complexity in disease architecture that might be shared among diverse clinical phenotypes.epistasis | ciliopathy | zebrafish | in vivo assays E xome and whole-genome resequencing is likely to catalyze a paradigm shift in the identification of genetic lesions in patients (1). At the same time, even within the confines of the coding genome, such technologies pose an interpretive problem, in that the pathogenic candidacy of mutations can only be derived by narrow genetic models and limited computational predictive tools, both of which are likely to under-and misinterpret the effect of some mutations. Moreover, inter-and intrafamilial variability, a phenomenon prevalent in most genetic traits, remains a major confounding factor because both allelic variation at a single locus and second-site trans modifiers can exert a significant influence on penetrance and expressivity through additive and epistatic effects (2).Bardet-Biedl Syndrome (BBS) is a useful model for dissecting epistasis because most of the 14 BBS genes can also contribute epistatic alleles (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). BBS is also a representative of the ciliopathy disease spectrum, a group of disorders characterized by defects in ciliary structure and/or ciliary signal output (18). Hallmarks of BBS include retinal degeneration, obesity, hypogonadism, polydactyly, renal dysfunction, and mental retardation (19).We and others have shown that the zebrafish provides experimentally tractable and physiologically relevant models of important aspects of ciliary dysfunction (2,15,17,(20)(21)(22)(23). Moreover, human mRNA for ciliopathy genes can rescue both morphant and mutant zebrafish phenotypes efficiently, providing a robust platform for interpretation of the pathological relevance of identified missense alleles, whose causal relation to the disorder cannot be proven definitively with genetic arguments alone (15,17,22,23).Here, we have integrated multiple independent in vivo assays, followed by in vitro validations, to int...

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Section: Resultsmentioning

confidence: 87%

Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet–Biedl syndrome

Zaghloul

Liu

Gerdes

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

109

145

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“…7,[33][34][35][36] As well as the phenotypic overlaps exhibited between ciliopathies, there is an emerging evidence suggesting that genes mutated in BBS and other ciliopathies exhibit some genetic overlap. 37 For example, mutations in BBS2, BBS4 and BBS6 have been identified in patients with Meckel syndrome. 38 Similarly, mutations in MKS1, which normally lead to Meckel syndrome, may be associated with a BBS phenotype and mutations in MKS3 have been identified in patients with BBS and Joubert syndrome.…”

Section: Genetic Basis Of the Diseasementioning

confidence: 99%

“…This supports the hypothesis that the BBS proteins interact in a common cellular process, thus making the genotypes clinically indistinguishable. 37 Submission of BBS gene variants to a public databases such as Mutadatabase (www.mutadatabase.org) may aid in further delineation of the genotype-phenotype correlation.…”

Section: Genetic Basis Of the Diseasementioning

confidence: 99%

Bardet–Biedl syndrome

2012

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“…[3][4][5] In addition, mutations in BBS patients have also been identified in MKS1 and CEP290, genes known to cause other ciliopathic phenotypes such as Meckel syndrome and nephronophthisis. 6 Owing to the large number of BBS genes, direct sequencing of all coding exons of these (135 exons for BBS1-12 and 23 exons for ALMS1) is not practical or cost-effective.…”

Section: Introductionmentioning

confidence: 99%

Arrayed primer extension technology simplifies mutation detection in Bardet–Biedl and Alström syndrome

Pereiro

Hoskins²,

Marshall

et al. 2010

Eur J Hum Genet

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Bardet-Biedl syndrome (BBS; OMIM no. 209 900) and Alströ m syndrome (ALMS; OMIM no. 203 800) are rare, multisystem genetic disorders showing both a highly variable phenotype and considerable phenotypic overlap; they are included in the emerging group of diseases called ciliopathies. The genetic heterogeneity of BBS with 14 causal genes described to date, serves to further complicate mutational analysis. The development of the BBS-ALMS array which detects known mutations in these genes has allowed us to detect at least one mutation in 40.5% of BBS families and in 26.7% of ALMS families validating this as an efficient and cost-effective first pass screening modality. Furthermore, using this method, we found two BBS families segregating three BBS alleles further supporting oligogenicity or modifier roles for additional mutations. We did not observe more than two mutations in any ALMS family.

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Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy

Cited by 334 publications

References 124 publications

Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet–Biedl syndrome

Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet–Biedl syndrome

Bardet–Biedl syndrome

Arrayed primer extension technology simplifies mutation detection in Bardet–Biedl and Alström syndrome

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