Bardet-Biedl syndrome-7 (<i>BBS7</i>) shows treatment potential and a cone-rod dystrophy phenotype that recapitulates the non-human primate model

Alemán, Tomás S.; O’Neil, Erin; O’Connor, Keli; Yu, Jinhui; Aleman, Isabella A.; Bennett, Jean; Morgan, Jessica Ijams Wolfing; Toussaint, Brian

doi:10.1080/13816810.2021.1888132

Cited by 11 publications

(12 citation statements)

References 116 publications

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“…2,23 Yet, there are studies were BBS7 patients present mild phenotypes. 24 Compared to BBS2, BBS7, and BBS9, BBS1 has been associated with a low occurrence of renal anomalies. 2 Conforming to these findings, we observed renal anomalies in 50% of our patients with BBS7, while it was seen in only 27% of the patients with BBS1.…”

Section: Discussionmentioning

confidence: 97%

A Genotype–Phenotype Analysis of the Bardet–Biedl Syndrome in Puerto Rico

Guardiola

Ramos

Izquierdo

et al. 2021

OPTH

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Background: Bardet-Biedl syndrome is a complex heterogeneous ciliopathy caused by genetic mutations. Although establishing genotype-phenotype correlations has been challenging, some regional variations have been previously reported. Due to its relative geographic isolation, Puerto Rico has a greater prevalence of Bardet-Biedl syndrome than do other regions. We sought to characterize the most frequent genotypic variations in a local cohort of Bardet-Biedl syndrome patients and report any genotypic-phenotypic trends. Methods: Twenty-seven patients from an ophthalmology clinic in Puerto Rico with genetically confirmed Bardet-Biedl syndrome took a questionnaire inquiring about their most common symptoms. Ophthalmological information was obtained from patient records. The frequencies of the genotypic variations and symptoms were calculated. Results: In the study population, BBS1 was the most prevalent mutated gene, followed by BBS7. In the BBS1 group, we found homozygotes for c.1169T>G (p.Met390Arg) and c.1645G>T (p. Glu549*), and compound heterozygotes for c.1169T>G (p.Met390Arg) and c.1645G>T (p. Glu549*), with one patient having c.1645G>T (p.Glu549*) and c.432+1G>A (splice donor). All the BBS7 patients were homozygous for c.632C>T (p.Thr211Ile). Compared to BBS7, we found that BBS1 patients generally had a milder ocular and systemic phenotype. However, when analyzing different BBS1 variants, patients with mutations in c.1645G>T (p.Glu549*), both compound heterozygous and homozygous, had more severe systemic phenotypes, overall. Conclusion:Our study was the first detailed genotype-phenotype analysis of the Bardet-Biedl syndrome in Puerto Rico. Genetic mutations in BBS1 and BBS7 seem to be the most common culprits behind Bardet-Biedl syndrome in this population. Although patients diagnosed with BBS1 are likely to display milder systemic features, this was not the case with our BBS1 patients having the c.1645G>T (p.Glu549*) mutation. Further studies should focus on the c.1645G>T (p.Glu549*) mutation's impact on the BBS1 gene and protein product.

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Section: Discussionmentioning

confidence: 97%

A Genotype–Phenotype Analysis of the Bardet–Biedl Syndrome in Puerto Rico

Guardiola

Ramos

Izquierdo

et al. 2021

OPTH

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“…The disrupted cone photoreceptor mosaic, dark patchy areas and clumping of the RPE demonstrate the severe dystrophy of the retina. A publication of two siblings with BBS due to a mutation in the BBS7 gene also observed a reduced photoreceptor density by adaptive optics scanning light ophthalmoscopy (AOSLO) [ 57 ]. Detection of changes in cone appearance in one patient could also show the further progression of degeneration.…”

Section: Discussionmentioning

confidence: 99%

Ophthalmic and Genetic Features of Bardet Biedl Syndrome in a German Cohort

Nasser

Kohl

Kurtenbach

et al. 2022

Genes

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The aim of this study was to characterize the ophthalmic and genetic features of Bardet Biedl (BBS) syndrome in a cohort of patients from a German specialized ophthalmic care center. Sixty-one patients, aged 5–56 years, underwent a detailed ophthalmic examination including visual acuity and color vision testing, electroretinography (ERG), visually evoked potential recording (VEP), fundus examination, and spectral domain optical coherence tomography (SD-OCT). Adaptive optics flood illumination ophthalmoscopy was performed in five patients. All patients had received diagnostic genetic testing and were selected upon the presence of apparent biallelic variants in known BBS-associated genes. All patients had retinal dystrophy with morphologic changes of the retina. Visual acuity decreased from ~0.2 (decimal) at age 5 to blindness 0 at 50 years. Visual field examination could be performed in only half of the patients and showed a concentric constriction with remaining islands of function in the periphery. ERG recordings were mostly extinguished whereas VEP recordings were reduced in about half of the patients. The cohort of patients showed 51 different likely biallelic mutations—of which 11 are novel—in 12 different BBS-associated genes. The most common associated genes were BBS10 (32.8%) and BBS1 (24.6%), and by far the most commonly observed variants were BBS10 c.271dup;p.C91Lfs*5 (21 alleles) and BBS1 c.1169T>G;p.M390R (18 alleles). The phenotype associated with the different BBS-associated genes and genotypes in our cohort is heterogeneous, with diverse features without genotype–phenotype correlation. The results confirm and expand our knowledge of this rare disease.

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“…The additional genetically validated and affected animals similarly displayed the range of deficits described in human BBS7 disease. Moreover, the retinal pathology involved loss of function of photoreceptors and closely parallels the disease progression described in human Bardet-Biedl Syndrome [ 111 , 112 ].…”

Section: Bardet-beidl Syndrome ( Bbs7 )mentioning

confidence: 80%

Nonhuman primate genetic models for the study of rare diseases

Vallender

Hotchkiss

Lewis

et al. 2023

Orphanet J Rare Dis

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Pre-clinical research and development relies heavily upon translationally valid models of disease. A major difficulty in understanding the biology of, and developing treatments for, rare disease is the lack of animal models. It is important that these models not only recapitulate the presentation of the disease in humans, but also that they share functionally equivalent underlying genetic causes. Nonhuman primates share physiological, anatomical, and behavioral similarities with humans resulting from close evolutionary relationships and high genetic homology. As the post-genomic era develops and next generation sequencing allows for the resequencing and screening of large populations of research animals, naturally occurring genetic variation in nonhuman primates with clinically relevant phenotypes is regularly emerging. Here we review nonhuman primate models of multiple rare genetic diseases with a focus on the similarities and differences in manifestation and etiologies across species. We discuss how these models are being developed and how they can offer new tools and opportunities for researchers interested in exploring novel therapeutics for these and other genetic diseases. Modeling human genetic diseases in translationally relevant nonhuman primates presents new prospects for development of therapeutics and a better understanding of rare diseases. The post-genomic era offers the opportunity for the discovery and further development of more models like those discussed here.

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Bardet-Biedl syndrome-7 (BBS7) shows treatment potential and a cone-rod dystrophy phenotype that recapitulates the non-human primate model

Cited by 11 publications

References 116 publications

A Genotype–Phenotype Analysis of the Bardet–Biedl Syndrome in Puerto Rico

A Genotype–Phenotype Analysis of the Bardet–Biedl Syndrome in Puerto Rico

Ophthalmic and Genetic Features of Bardet Biedl Syndrome in a German Cohort

Nonhuman primate genetic models for the study of rare diseases

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