Liver anomalies as a phenotype parameter of Bardet–Biedl syndrome

Day, Leora Branfield; Quammie, Claudia; Hèon, Elise; Bhan, Aparna; Batmanabane, Vaishnavi; Dai, Tao; Kamath, Binita M.

doi:10.1111/cge.12684

Cited by 16 publications

(13 citation statements)

References 9 publications

(7 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2B ). As reported in BBS patients ( 28 ), Bbs2 −/− mice exhibited several liver abnormalities including elevated liver weight, which was reduced to WT levels with GCSi treatment. Serum alanine transaminase (ALT) and triglycerides were significantly increased albeit within normal range in Bbs2 −/− mice and were reduced to WT levels by GCS inhibition ( Fig.…”

Section: Resultssupporting

confidence: 68%

“…Adipose tissue dysfunction is observed in non-alcoholic hepatic steatosis ( 45 ). Similarly, the liver phenotype in BBS patients is associated with obesity and overlaps with the manifestations of non-alcoholic fatty liver disease ( 28 ). Bbs2 −/− mice showed elevated levels of serum triglycerides, ALT and increased liver weight, which were reduced by GCS inhibition.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Correction of cilia structure and function alleviates multi-organ pathology in Bardet–Biedl syndrome mice

Husson

Bukanov

Moreno

et al. 2020

Human Molecular Genetics

View full text Add to dashboard Cite

Abstract Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive ciliopathy affecting multiple organs. The development of potential disease-modifying therapy for BBS will require concurrent targeting of multi-systemic manifestations. Here, we show for the first time that monosialodihexosylganglioside accumulates in Bbs2−/− cilia, indicating impairment of glycosphingolipid (GSL) metabolism in BBS. Consequently, we tested whether BBS pathology in Bbs2−/− mice can be reversed by targeting the underlying ciliary defect via reduction of GSL metabolism. Inhibition of GSL synthesis with the glucosylceramide synthase inhibitor Genz-667 161 decreases the obesity, liver disease, retinal degeneration, and olfaction defect in Bbs2−/− mice. These effects are secondary to preservation of ciliary structure and signaling, and stimulation of cellular differentiation. In conclusion, reduction of GSL metabolism resolves the multi-organ pathology of Bbs2−/− mice by directly preserving ciliary structure and function towards a normal phenotype. Since this approach does not rely on the correction of the underlying genetic mutation, it might translate successfully as a treatment for other ciliopathies.

show abstract

Section: Resultssupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Correction of cilia structure and function alleviates multi-organ pathology in Bardet–Biedl syndrome mice

Husson

Bukanov

Moreno

et al. 2020

Human Molecular Genetics

View full text Add to dashboard Cite

show abstract

“…The literature search was performed according to the protocol preregistered in Prospero (CRD42018096099) and it followed the PRISMA guidelines whenever applicable (Table S1 and Figure S1). In total, we identified 85 relevant studies (Abu Safieh et al, ; Agha et al, ; Ajmal et al, ; Al‐Hamed et al, ; Alazami et al, ; Aldahmesh et al, ; Azari et al, ; Badano, ; Baker et al, ; Bee, Chawla, & Zhao, ; Bennouna‐Greene et al, ; Billingsley et al, ; Billingsley, Vincent, Deveault, & Heon, ; Branfield Day et al, ; Braun et al, ; Bujakowska et al, ; Castro‐Sanchez et al, ; Chaki et al, ; Chul Yoon et al, ; Cox et al, ; Davies, ; Deveault et al, ; Ece Solmaz et al, ; Esposito et al, ; Estrada‐Cuzcano, Koenekoop, et al, ; Estrada‐Cuzcano, Neveling, et al, ; Fan et al, ; Fattahi et al, ; Fedick et al, ; Frank et al, ; Gerth, Zawadzki, Werner, & Heon, ; Ghadami et al, ; González‐del Pozo et al, ; Harville et al, ; Heon et al, ; Hjortshoj, Gronskov, Brondum‐Nielsen, & Rosenberg, ; Hjortshoj et al, ; Hulleman et al, ; Iannaccone et al, ; Innes et al, ; Iurian, Arts, Brunner, & Fintina, ; Janssen et al, ; Kamme, Mayer, Strom, Andréasson, & Weisschuh, ; Katsanis et al, ; Katsanis et al, ; Kerr, Bhan, & Héon, ; A. O. Khan, Decker, Bachmann, Bolz, & Bergmann, ; S. Khan et al, , S. A. Khan et al, ; Laurier et al, ; Leitch et al, ; Lim et al, ; Lindstrand et al, ; Lindstrand et al, ; M'Hamdi et al, ; Maria et al,…”

Section: Resultsmentioning

confidence: 99%

Meta‐analysis of genotype‐phenotype associations in Bardet‐Biedl syndrome uncovers differences among causative genes

et al. 2019

View full text Add to dashboard Cite

Bardet‐Biedl syndrome (BBS) is a recessive genetic disease causing multiple organ anomalies. Most patients carry mutations in genes encoding for the subunits of the BBSome, an octameric ciliary transport complex, or accessory proteins involved in the BBSome assembly or function. BBS proteins have been extensively studied using in vitro, cellular, and animal models. However, the molecular functions of particular BBS proteins and the etiology of the BBS symptoms are still largely elusive. In this study, we applied a meta‐analysis approach to study the genotype‐phenotype association in humans using our database of all reported BBS patients. The analysis revealed that the identity of the causative gene and the character of the mutation partially predict the clinical outcome of the disease. Besides their potential use for clinical prognosis, our analysis revealed functional differences of particular BBS genes in humans. Core BBSome subunits BBS2, BBS7, and BBS9 manifest as more critical for the function and development of kidneys than peripheral subunits BBS1, BBS4, and BBS8/TTC8, suggesting that incomplete BBSome retains residual function at least in the kidney.

show abstract

“…Bardet‐Biedl syndrome (BBS:MIM209900) is a complex disease characterized mainly by severe photoreceptor degeneration, truncal obesity, postaxial polydactyly, autism‐like behavior, cognitive impairment, hypogonadism, renal anomalies, among other secondary features (Gerth, Zawadzki, Werner, & Heon, ; Habibullah & Mohiuddin, ; Heon et al, ; Kerr, Bhan, & Heon, ; Weihbrecht et al, ). BBS is phenotypically and genetically heterogeneous, and demonstrates considerable overlap with other ciliopathies such as Joubert syndrome (JBST) (Beales, Elcioglu, Woolf, Parker, & Flinter, ; Billingsley et al, ; Branfield Day et al, ; Deveault et al, ; Gerth et al, ; Heon et al, ; Kerr et al, ). Biallelic mutations have been identified in at least 21 BBS genes (Heon et al, ; Khan et al, ), all of which are involved in primary cilia structure and/or function (Alvarez‐Satta, Castro‐Sanchez, & Valverde, ; Khan et al, ).…”

Section: Brief Reportmentioning

confidence: 99%

Retrotransposon insertion as a novel mutational event in Bardet‐Biedl syndrome

Tavares

Tang

Vig

et al. 2018

Molec Gen & Gen Med

View full text Add to dashboard Cite

Background Bardet‐Biedl syndrome (BBS) is an autosomal recessive pleiotropic disorder of the primary cilia that leads to severe visual loss in the teenage years. Approximately 80% of BBS cases are explained by mutations in one of the 21 identified genes. Documented causative mutation types include missense, nonsense, copy number variation (CNV), frameshift deletions or insertions, and splicing variants. Methods Whole genome sequencing was performed on a patient affected with BBS for whom no mutations were identified using clinically approved genetic testing of the known genes. Analysis of the WGS was done using internal protocols and publicly available algorithms. The phenotype was defined by retrospective chart review. Results We document a female affected with BBS carrying the most common BBS1 mutation ( BBS1 : Met390Arg) on the maternal allele and an insertion of a ~1.7‐kb retrotransposon in exon 13 on the paternal allele. This retrotransposon insertion was not automatically annotated by the standard variant calling protocols used. This novel variant was identified by visual inspection of the alignment file followed by specific genome analysis with an available algorithm for transposable elements. Conclusion This report documents a novel mutation type associated with BBS and highlights the importance of systematically performing transposon detection analysis on WGS data of unsolved cases.

show abstract

Liver anomalies as a phenotype parameter of Bardet–Biedl syndrome

Cited by 16 publications

References 9 publications

Correction of cilia structure and function alleviates multi-organ pathology in Bardet–Biedl syndrome mice

Correction of cilia structure and function alleviates multi-organ pathology in Bardet–Biedl syndrome mice

Meta‐analysis of genotype‐phenotype associations in Bardet‐Biedl syndrome uncovers differences among causative genes

Retrotransposon insertion as a novel mutational event in Bardet‐Biedl syndrome

Contact Info

Product

Resources

About