BBS7andTTC8(BBS8) mutations play a minor role in the mutational load of Bardet-Biedl syndrome in a multiethnic population

Bin, Jenea; Madhavan, Jagadeesan; Ferrini, W.; Mok, Calvin; Billingsley, Gail; Hèon, Elise

doi:10.1002/humu.21040

Cited by 38 publications

(27 citation statements)

References 28 publications

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“…A second example is provided by family KFSH-F006 in which both patients demonstrate reduced efficiency of intron 10 exclusion despite having normal genomic sequence of the entire intron 10 as well as the flanking exons, which again suggests a deep intronic mutation involving an upstream or downstream intron (figure 2). These results suggest that the current estimate that all currently known BBS genes only account for 75% of the genetics of this condition16 may be an underestimate because most previous mutation reports relied on DNA only. Another noteworthy outcome of this study is that our data support growing consensus that triallelic inheritance of BBS is exceptionally rare.…”

Section: Discussionmentioning

confidence: 73%

Clinical and molecular characterisation of Bardet-Biedl syndrome in consanguineous populations: the power of homozygosity mapping

Safieh

Aldahmesh

Shamseldin

et al. 2009

Journal of Medical Genetics

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Bardet-Biedl syndrome (BBS) is a ciliopathy with pleiotropic effect that manifests primarily as renal insufficiency, polydactyly, retinal dystrophy and obesity. The current phenotype-genotype correlation is insufficient to predict the likely causative mutation that makes sequencing of all 14 BBS genes an often necessary but highly complicated way to identify the underlying genetic defect in affected patients. In this study, homozygosity mapping is shown as a robust approach that is highly suited for genetically heterogeneous autosomal recessive disorders in populations in which consanguinity is prevalent. This approach allowed us to quickly identify seven novel mutations in seven families with BBS. Some of these mutations would have been missed by unguided routine sequencing, which suggests that missed mutations in known BBS genes could be more common than previously thought. This study, the largest to date on Saudi BBS families, also revealed interesting phenotypic aspects of BBS, including the first report of non-syndromic retinitis pigmentosa as a novel BBS phenotype.

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Section: Discussionmentioning

confidence: 73%

Clinical and molecular characterisation of Bardet-Biedl syndrome in consanguineous populations: the power of homozygosity mapping

Safieh

Aldahmesh

Shamseldin

et al. 2009

Journal of Medical Genetics

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“…TPR domains are involved in many cellular processes including the assembly of multiprotein complexes21. Disorders resulting from mutations in genes that encode TPR-containing proteins include Fanconi anaemia22, Leber’s congenital amaurosis23, Bardet-Biedl syndrome24, peroxisome biogenesis disorders25, chronic granulomatous disease26, and Charcot-Marie-Tooth disease type C27. Nevertheless relatively little is known about the normal function of proteins that contain TPR domains and about the pathogenesis of conditions in which these proteins are lacking or abnormal.…”

Section: Discussionmentioning

confidence: 99%

Mutations in TTC37 Cause Trichohepatoenteric Syndrome (Phenotypic Diarrhea of Infancy)

et al. 2010

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Background Trichohepatoenteric syndrome (THES) is an autosomal recessive disorder characterised by life-threatening diarrhoea in infancy, immunodeficiency, liver disease, trichorrhexis nodosa, facial dysmorphism, hypopigmentation and cardiac defects. We attempted to characterise the phenotype and elucidate the molecular basis of THES. Methods Twelve patients with classical THES from 11 families had detailed phenotyping. Autozygosity mapping was undertaken in 8 patients from consanguineous families using 250k single nucleotide polymorphism (SNP) arrays and linked regions evaluated using microsatellite markers. Linkage was confirmed to one region from which candidate genes were analysed. The effect of mutations on protein production and/or localisation in hepatocytes and intestinal epithelial cells from affected patients was characterised by immunohistochemistry. Results Previously unrecognised platelet abnormalities (reduced platelet α-granules, unusual stimulated alpha granule content release, abnormal lipid inclusions, abnormal platelet canalicular system and reduced number of microtubules) were identified. The THES locus was mapped to 5q14.3 – 5q21.2. Sequencing of candidate genes demonstrated mutations in TTC37, which encodes the uncharacterised tetratricopeptide repeat protein, thespin. Bioinformatic analysis suggested thespin to be involved in protein-protein interactions or chaperone. Preliminary studies of enterocyte brush-border ion transporter proteins (NHE2, NHE3, Aquaporin 7, Na/I symporter and H / K ATPase) showed reduced expression or mislocalisation in all THES patients with different profiles for each. In contrast the basolateral localisation of Na/K ATPase was not altered. Conclusion THES is caused by mutations in TTC37. TTC37 mutations have a multisystem effect which may be due to abnormal stability and / or intracellular localisation of TTC37 target proteins.

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“…BBS8 was recently shown play a role in establishing planar cell polarity and orientation of cilia in epithelial cells (22). To date, six mutations in the BBS8 gene have been linked to classical BBS (18,23,24). An exception to this pattern is the BBS8 IVS1-2AϾG mutation, which disrupts the 3= splice site of BBS8 exon 2A and causes nonsyndromic RP.…”

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confidence: 99%

Alternative Splicing Shapes the Phenotype of a Mutation in BBS8 To Cause Nonsyndromic Retinitis Pigmentosa

Murphy

Singh

Kolandaivelu

et al. 2015

Molecular and Cellular Biology

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Bardet-Biedl syndrome (BBS) is a genetic disorder affecting multiple systems and organs in the body. Several mutations in genes associated with BBS affect only photoreceptor cells and cause nonsyndromic retinitis pigmentosa (RP), raising the issue of why certain mutations manifest as a systemic disorder whereas other changes in the same gene affect only a specific cell type. Here, we show that cell-type-specific alternative splicing is responsible for confining the phenotype of the A-to-G substitution in the 3= splice site of BBS8 exon 2A (IVS1-2A>G mutation) in the BBS8 gene to photoreceptor cells. The IVS1-2A>G mutation leads to missplicing of BBS8 exon 2A, producing a frameshift in the BBS8 reading frame and thus eliminating the protein specifically in photoreceptor cells. Cell types other than photoreceptors skip exon 2A from the mature BBS8 transcript, which renders them immune to the mutation. We also show that the splicing of Bbs8 exon 2A in photoreceptors is directed exclusively by redundant splicing enhancers located in the adjacent introns. These intronic sequences are sufficient for photoreceptor-cell-specific splicing of heterologous exons, including an exon with a randomized sequence. The BBSome is a multiprotein complex that is thought be required for the transport of proteins in and out of the cilia. The BBSome interacts with intraflagellar transport A (IFT-A) and IFT-B complexes and promotes the assembly of the IFT machinery (1-7). Several proteins, such as the G-protein-coupled receptors Smo, Sstr3, Mchr1, and Vipr2, depend on the BBSome for their ciliary transport, suggesting a possible role for the BBSome as an adapter that connects the IFT complex to its cargo in primary cilia (2,8,9). Mutations in genes that encode BBSome components and proteins associated with the BBSome are linked to systemic Bardet-Biedl syndrome (BBS). BBS is an autosomal recessive ciliopathy caused by defects in the BBSome that disrupt the normal ciliary function throughout the body. BBS symptoms include retinitis pigmentosa (RP), skeletal malformations, mental retardation, obesity, hearing impairment, shortened limbs, polydactyly, and kidney cysts (10, 11). In photoreceptor cells, BBSome deficiency leads to defects in rod outer-segment formation and localization of rod opsin and, ultimately, photoreceptor cell death (10-13). The severity of the BBS symptoms can vary considerably due to the nature of the mutation and the genetic background. Interestingly, phenotypes of different mutations in the same gene can range from a classical BBS that affects multiple systems to nonsyndromic RP, where the phenotype is limited to loss of photoreceptor function. For example, the ARL6 (BBS3) A89V, BBS1 M390R, and BBS8 IVS1-2AϾG mutations cause nonsyndromic RP, while several other mutations in the same genes manifest as classical BBS, presenting additional symptoms such as obesity, hearing impairment, polydactyly, and mental retardation in addition to the loss of vision (7,(14)(15)(16)(17)(18)(19). The existence of BBSome mutations th...

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BBS7andTTC8(BBS8) mutations play a minor role in the mutational load of Bardet-Biedl syndrome in a multiethnic population

Cited by 38 publications

References 28 publications

Clinical and molecular characterisation of Bardet-Biedl syndrome in consanguineous populations: the power of homozygosity mapping

Clinical and molecular characterisation of Bardet-Biedl syndrome in consanguineous populations: the power of homozygosity mapping

Mutations in TTC37 Cause Trichohepatoenteric Syndrome (Phenotypic Diarrhea of Infancy)

Alternative Splicing Shapes the Phenotype of a Mutation in BBS8 To Cause Nonsyndromic Retinitis Pigmentosa

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