Bardet-Biedl Syndrome as a Chaperonopathy: Dissecting the Major Role of Chaperonin-Like BBS Proteins (BBS6-BBS10-BBS12)

Álvarez-Satta, María; Castro-Sánchez, Sheila; Valverde, Diana

doi:10.3389/fmolb.2017.00055

Cited by 56 publications

(94 citation statements)

References 55 publications

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“…Acquired chaperonopathies are due to non-genetic chaperone defects such as defective post-translational modifications or mis regulated gene expression (Macario, 2007;Lupo et al, 2016). A few examples of known chaperonopathies include dominant distal myopathy (Hsp40), hypomyelinating distrophy (Hsp60), Charcot-Marie-Tooth disease (Hsp27), and Bardet-Biedl syndrome (BBS proteins) (Lupo et al, 2016;Álvarez-Satta et al, 2017;Palmio et al, 2020;Sarparanta et al, 2020). The mtHsp60 gene has been localized to chromosome 2 in humans.…”

Section: Chaperonopathies and The Role Of Mthsp60 In Diseasementioning

confidence: 99%

Complex Destabilization in the Mitochondrial Chaperonin Hsp60 Leads to Disease

Rodrı́guez

Salzen

Holguin

et al. 2020

Front. Mol. Biosci.

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Several neurological disorders have been linked to mutations in chaperonin genes and more specifically to the HSPD1 gene. In humans, HSPD1 encodes the mitochondrial Heat Shock Protein 60 (mtHsp60) chaperonin, which carries out essential protein folding reactions that help maintain mitochondrial and cellular homeostasis. It functions as a macromolecular complex that provides client proteins an environment that favors proper folding in an ATP-dependent manner. It has been established that mtHsp60 plays a crucial role in the proper folding of mitochondrial proteins involved in ATP producing pathways. Recently, various single-point mutations in the mtHsp60 encoding gene have been directly linked to neuropathies and paraplegias. Individuals who harbor mtHsp60 mutations that negatively impact its folding ability display phenotypes with highly compromised muscle and neuron cells. Carriers of these mutations usually develop neuropathies and paraplegias at different stages of their lives mainly characterized by leg stiffness and weakness as well as degeneration of spinal cord nerves. These phenotypes are likely due to hindered energy producing pathways involved in cellular respiration resulting in ATP deprived cells. Although the complete protein folding mechanism of mtHsp60 is not well understood, recent work suggests that several of these mutations act by destabilizing the oligomeric stability of mtHsp60. Here, we discuss recent studies that highlight key aspects of the mtHsp60 mechanism with a focus on some of the known disease-causing point mutations, D29G and V98I, and their effect on the protein folding reaction cycle.

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Section: Chaperonopathies and The Role Of Mthsp60 In Diseasementioning

confidence: 99%

Complex Destabilization in the Mitochondrial Chaperonin Hsp60 Leads to Disease

Rodrı́guez

Salzen

Holguin

et al. 2020

Front. Mol. Biosci.

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“…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, ). Approximately 80% of the clinically examined BBS cases (Forsythe & Beales, ) have been associated with biallelic mutations in one of the 21 BBS genes, of which Bardet‐Biedl syndrome‐1 gene ( BBS1: 209,901) is the most frequently mutated (Billingsley, Deveault, & Heon, ).…”

Section: Brief Reportmentioning

confidence: 99%

“…Heon et al, 2016;Kerr et al, 2015). Biallelic mutations have been identified in at least 21 BBS genes (Heon et al, 2016;Khan et al, 2016), all of which are involved in primary cilia structure and/or function (Alvarez-Satta, Castro-Sanchez, & Valverde, 2017;Khan et al, 2016). Approximately 80% of the clinically examined BBS cases (Forsythe & Beales, 2015) have been associated with biallelic mutations in one of the 21 BBS genes, of which Bardet-Biedl syndrome-1 gene (BBS1: 209,901) is the most frequently mutated .…”

mentioning

confidence: 99%

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

Tavares

Tang

Vig

et al. 2018

Molec Gen & Gen Med

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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.

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“…The syndrome has a genetic origin, and to date 21 genes have been associated with human BBS but it is presumable that other unknown genes are yet to be discovered [1]. Even though many efforts have been devoted to address genotype-phenotype correlation, there is still little information on this issue [2-4].…”

Section: Introductionmentioning

confidence: 99%

Urine Proteomics Revealed a Significant Correlation Between Urine-Fibronectin Abundance and Estimated-GFR Decline in Patients with Bardet-Biedl Syndrome

Caterino

Zacchia

Costanzo

et al. 2018

Kidney Blood Press Res

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Background:/Aims: Renal disease is a common cause of morbidity in patients with Bardet-Biedl syndrome (BBS), however the severity of kidney dysfunction is highly variable. To date, there is little information on the pathogenesis, the risk and predictor factors for poor renal outcome in this setting. The present study aims to analyze the spectrum of urinary proteins in BBS patients, in order to potentially identify 1) disease-specific proteomic profiles that may differentiate the patients from normal subjects; 2) urinary markers of renal dysfunction. Methods: Fourteen individuals (7 males and 7 females) with a clinical diagnosis of BBS have been selected in this study. A pool of 10 aged-matched males and 10 aged-matched females have been used as controls for proteomic analysis. The glomerular filtration rate (eGFR) has been estimated using the CKD-EPI formula. Variability of eGFR has been retrospectively assessed calculating average annual eGFR decline (ΔeGFR) in a mean follow-up period of 4 years (3-7). Results: 42 proteins were significantly over- or under-represented in BBS patients compared with controls; the majority of these proteins are involved in fibrosis, cell adhesion and extracellular matrix organization. Statistic studies revealed a significant correlation between urine fibronectin (u-FN) (r²=0.28; p<0.05), CD44 antigen (r² =0.35; p<0.03) and lysosomal alfa glucosidase ( r²0.27; p<0.05) abundance with the eGFR. In addition, u-FN (r² =0.2389; p<0.05) was significantly correlated with ΔeGFR. Conclusion: The present study demonstrates that urine proteome of BBS patients differs from that of normal subjects; in addition, kidney dysfunction correlated with urine abundance of known markers of renal fibrosis.

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Bardet-Biedl Syndrome as a Chaperonopathy: Dissecting the Major Role of Chaperonin-Like BBS Proteins (BBS6-BBS10-BBS12)

Cited by 56 publications

References 55 publications

Complex Destabilization in the Mitochondrial Chaperonin Hsp60 Leads to Disease

Complex Destabilization in the Mitochondrial Chaperonin Hsp60 Leads to Disease

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

Urine Proteomics Revealed a Significant Correlation Between Urine-Fibronectin Abundance and Estimated-GFR Decline in Patients with Bardet-Biedl Syndrome

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