Evaluation of Visual Function and Needs in Adult Patients With Bardet–biedl Syndrome

Denniston, Alastair K; Beales, Philip L.; Tomlins, Paul J.; Good, Peter; Langford, M J; Foggensteiner, Lukas; Williams, Denise; Tsaloumas, M D

doi:10.1097/iae.0000000000000222

Cited by 28 publications

(23 citation statements)

References 17 publications

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“…BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9 and BBS18 comprise the BBSome, a highly conserved protein complex that plays a critical role in regulating cilia protein trafficking and IFT [17] , [18] , [19] , [20] , [21] , [22] . Variants in BBS2 (OMIM# 606151 ) are responsible for 8-18% of BBS cases and cause a more severe retinal phenotype compared to BBS1 [23] , [24] , [25] , [26] , [27] . The BBS2 gene spans ~53 kb on chromosome 16q13, is comprised of 17 exons and encodes a 721-amino acid protein [27] .…”

Section: Introductionmentioning

confidence: 99%

Translational readthrough of ciliopathy genes BBS2 and ALMS1 restores protein, ciliogenesis and function in patient fibroblasts

Eintracht¹,

Forsythe

May-Simera³

et al. 2021

EBioMedicine

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Background Ciliary dysfunction underlies a range of genetic disorders collectively termed ciliopathies, for which there are no treatments available. Bardet-Biedl syndrome (BBS) is characterised by multisystemic involvement, including rod-cone dystrophy and renal abnormalities. Together with Alström syndrome (AS), they are known as the ‘obesity ciliopathies’ due to their common phenotype. Nonsense mutations are responsible for approximately 11% and 40% of BBS and AS cases, respectively. Translational readthrough inducing drugs (TRIDs) can restore full-length protein bypassing in-frame premature termination codons, and are a potential therapeutic approach for nonsense-mediated ciliopathies. Methods Patient fibroblasts harbouring nonsense mutations from two different ciliopathies (Bardet-Biedl Syndrome and Alström Syndrome) were treated with PTC124 (ataluren) or amlexanox. Following treatment, gene expression, protein levels and ciliogenesis were evaluated. The expression of intraflagellar transport protein IFT88 and G-protein coupled receptor SSTR3 was investigated as a readout of ciliary function. Findings mRNA expression was significantly increased in amlexanox-treated patient fibroblasts, and full-length BBS2 or ALMS1 protein expression was restored in PTC124- and amlexanox-treated fibroblasts. Treatment with TRIDs significantly improved ciliogenesis defects in BBS2 Y24*/R275* fibroblasts. Treatment recovered IFT88 expression and corrected SSTR3 mislocalisation in BBS2 Y24*/R275* and ALMS1 S1645*/S1645* fibroblasts, suggesting rescue of ciliary function. Interpretation The recovery of full-length BBS2 and ALMS1 expression and correction of anatomical and functional ciliary defects in BBS2 Y24*/R275* and ALMS1 S1645*/S1645* fibroblasts suggest TRIDs are a potential therapeutic option for the treatment of nonsense-mediated ciliopathies.

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Section: Introductionmentioning

confidence: 99%

Translational readthrough of ciliopathy genes BBS2 and ALMS1 restores protein, ciliogenesis and function in patient fibroblasts

Eintracht¹,

Forsythe

May-Simera³

et al. 2021

EBioMedicine

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“…In this patient, we also found Hutchinson‐like upper central incisors finding that were not previously defined in BBS6 patients (Figure 3). In other patients where this mutation was observed, the sign of Hutchinson‐like upper central incisors was not defined, although dental anomaly was identified (Denniston et al., 2014; Riazuddin et al., 2017; Ullah et al., 2018). Our Patient 4 is a 5‐year‐old male patient with obesity, polydactyly, severe ID, renal and genital anomalies.…”

Section: Discussionmentioning

confidence: 99%

Clinical and exome sequencing findings in seven children with Bardet–Biedl syndrome from Turkey

Gümüş

Tunçez

Öz

et al. 2020

Annals of Human Genetics

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Background Bardet–Biedl syndrome (BBS) is a very‐rare autosomal recessive genetic disorder with severe multisystem manifestations. Genetic testing plays an important role in the early diagnosis of the disease. In this study, while trying to elucidate the genetic etiology of seven individuals with clinical BBS diagnosis from six different families, we also aimed to examine the distribution of BBS variations in this region of Turkey. Methods and materials Exome sequencing analysis is performed for clinically diagnosed patients with BBS in the present study followed by parental segregation. The unreported and previously described clinical features are presented. Results Homozygous variants, four of which are unreported, in BBS‐related genes (BBS5 [c.682‐2A > G], MKKS [c.775del], BBS7 [c.849+1G > T], BBS9 [c.965G > A], BBS10 [c.145C > T], LZTFL1[c.384G > A]) are detected for all the seven individuals included in the study. The most common clinical finding is polydactyly followed by renal anomalies. The clinical features not previously described are correlated to the unreported variant. Conclusions In this study, exome sequencing findings are discussed and four previously unreported disease‐associated variants are described including the fifth BBS‐implicated LZTFL1 change and possible genotype–phenotype correlation is described.

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“…One of the most important features of BBS is the rod-cone dystrophy, affecting 94–100% of individuals [ 21 , 22 ]. The patients can present night blindness, peripheral vision loss, diminution of color, and overall loss of visual acuity [ 23 ].…”

Section: Pleiotropy and Variable Expressivity In Bardet–biedl Syndromementioning

confidence: 99%

Bardet–Biedl Syndrome—Multiple Kaleidoscope Images: Insight into Mechanisms of Genotype–Phenotype Correlations

Florea

Caba

Gorduza

2021

Genes

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Bardet–Biedl Syndrome is a rare non-motile primary ciliopathy with multisystem involvement and autosomal recessive inheritance. The clinical picture is extremely polymorphic. The main clinical features are retinal cone-rod dystrophy, central obesity, postaxial polydactyly, cognitive impairment, hypogonadism and genitourinary abnormalities, and kidney disease. It is caused by various types of mutations, mainly in genes encoding BBSome proteins, chaperonins, and IFT complex. Variable expressivity and pleiotropy are correlated with the existence of multiple genes and variants modifiers. This review is focused on the phenomena of heterogeneity (locus, allelic, mutational, and clinical) in Bardet–Biedl Syndrome, its mechanisms, and importance in early diagnosis and proper management.

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Evaluation of Visual Function and Needs in Adult Patients With Bardet–biedl Syndrome

Abstract: The BBS Ophthalmic Assessment Tool provides a wide-ranging assessment of ophthalmic status and vision-related needs of the BBS population. This evaluation demonstrates the spectrum of visual disability in this population and its correlation with worsening retinopathy over time.

Cited by 28 publications

References 17 publications

Translational readthrough of ciliopathy genes BBS2 and ALMS1 restores protein, ciliogenesis and function in patient fibroblasts

Translational readthrough of ciliopathy genes BBS2 and ALMS1 restores protein, ciliogenesis and function in patient fibroblasts

Clinical and exome sequencing findings in seven children with Bardet–Biedl syndrome from Turkey

Bardet–Biedl Syndrome—Multiple Kaleidoscope Images: Insight into Mechanisms of Genotype–Phenotype Correlations

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