Retinal Disease Expression in Bardet-Biedl Syndrome-1 (<i>BBS1</i>) Is a Spectrum from Maculopathy to Retina-Wide Degeneration

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Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder that results in retinal degeneration, obesity, cognitive impairment, polydactyly, renal abnormalities, and hypogenitalism. Of the 12 known BBS genes, BBS1 is the most commonly mutated, and a single missense mutation (M390R) accounts for Ϸ80% of BBS1 cases. To gain insight into the function of BBS1, we generated a Bbs1 M390R/M390R knockin mouse model. Mice homozygous for the M390R mutation recapitulated aspects of the human phenotype, including retinal degeneration, male infertility, and obesity. The obese mutant mice were hyperphagic and hyperleptinemic and exhibited reduced locomotor activity but no elevation in mean arterial blood pressure. Morphological evaluation of Bbs1 mutant brain neuroanatomy revealed ventriculomegaly of the lateral and third ventricles, thinning of the cerebral cortex, and reduced volume of the corpus striatum and hippocampus. Similar abnormalities were also observed in the brains of Bbs2 ؊/؊ , Bbs4 ؊/؊ , and Bbs6 ؊/؊ mice, establishing these neuroanatomical defects as a previously undescribed BBS mouse model phenotype. Ultrastructural examination of the ependymal cell cilia that line the enlarged third ventricle of the Bbs1 mutant brains showed that, whereas the 9 ؉ 2 arrangement of axonemal microtubules was intact, elongated cilia and cilia with abnormally swollen distal ends were present. Together with data from transmission electron microscopy analysis of photoreceptor cell connecting cilia, the Bbs1 M390R mutation does not affect axonemal structure, but it may play a role in the regulation of cilia assembly and/or function.B ardet-Biedl syndrome [BBS, Online Mendelian Inheritance in Man (OMIM) 209900] is a genetically heterogeneous autosomal recessive disorder characterized by obesity, retinal degeneration, polydactyly, cognitive impairment, hypogenitalism, and renal abnormalities, as well as susceptibility to hypertension, diabetes mellitus, olfaction deficits, and congenital cardiac defects. Twelve BBS genes (BBS1-12) have been identified to date (1-14). They encode a set of proteins thought to play a role in the structure or function of cilia, basal bodies, and intracellular transport (15, 16). Mutations in BBS1 are the most commonly observed in BBS. A single missense mutation that converts a methionine codon to an arginine codon (M390R) accounts for Ϸ80% of BBS1 mutations and is involved in 25% of all BBS cases (5). The M390R mutation occurs near predicted regions of coiled-coil protein domains and lies within a conserved predicted WD40-like protein motif. These protein motifs are involved in such basic biological processes as signal transduction, RNA synthesis/processing, chromatin assembly, vesicular trafficking, cytoskeletal assembly, cell cycle control, and apoptosis (17).Recently, BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, and BBS9 were shown to form a stable Ϸ450-kDa protein complex called the BBSome in cultured retinal pigment epithelial (RPE) cells and mouse testes. Depletion of some components of the BBSome, ...

Section: Discussionsupporting

confidence: 88%

A knockin mouse model of the Bardet–Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity

Davis

Swiderski

Rahmouni³

et al. 2007

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310

“…This suggestion is consistent with our impression that morphological deformities increased as epithelia aged in culture. It also agrees with the phenotype in BBS patients and mice where cilia form, but progressively deteriorate; an example is the photoreceptor cells that show progressive destruction over time (31,32). The presence of motile cilia in Bbs airway epithelia contrasts with the absence of flagella in sperm from Bbs mice (9-12).…”

Section: Discussionsupporting

confidence: 70%

Loss of Bardet–Biedl syndrome proteins alters the morphology and function of motile cilia in airway epithelia

Shah

Farmen²,

Moninger³

et al. 2008

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Mutations in a group of genes that contribute to ciliary function cause Bardet-Biedl syndrome (BBS). Most studies of BBS have focused on primary, sensory cilia. Here, we asked whether loss of BBS proteins would also affect motile cilia lining the respiratory tract. We found that BBS genes were expressed in human airway epithelia, and BBS2 and BBS4 localized to cellular structures associated with motile cilia. Although BBS proteins were not required for ciliogenesis, their loss caused structural defects in a fraction of cilia covering mouse airway epithelia. The most common abnormality was bulges filled with vesicles near the tips of cilia. We discovered this same misshapen appearance in airway cilia from Bbs1, Bbs2, Bbs4, and Bbs6 mutant mice. The structural abnormalities were accompanied by functional defects; ciliary beat frequency was reduced in Bbs mutant mice. Previous reports suggested BBS might increase the incidence of asthma. However, compared with wild-type controls, neither airway hyperresponsiveness nor inflammation increased in Bbs2 Ϫ/Ϫ or Bbs4 ؊/؊ mice immunized with ovalbumin. Instead, these animals were partially protected from airway hyperresponsiveness. These results emphasize the role of BBS proteins in both the structure and function of motile cilia. They also invite additional scrutiny of motile cilia dysfunction in patients with this disease.asthma ͉ basal body

“…An important prerequisite for gene therapy, however, is a timely genetic diagnosis before extensive photoreceptor death has occurred. Clinical studies suggest that among BBS1 patients, only half will have visual acuity of 20/60 or better at the time of diagnosis; the situation seems to be worse for those with BBS10 (37,38). This underscores the importance of BBS awareness in the ophthalmology and broader medical communities.…”

Section: Discussionmentioning

confidence: 99%

Gene therapy prevents photoreceptor death and preserves retinal function in a Bardet-Biedl syndrome mouse model

Simons

Boye

Hauswirth

et al. 2011

Patients with Bardet-Biedl syndrome (BBS) experience severe retinal degeneration as a result of impaired photoreceptor transport processes that are not yet fully understood. To date, there is no effective treatment for BBS-associated retinal degeneration, and blindness is imminent by the second decade of life. Here we report the development of an adeno-associated viral (AAV) vector that rescues rhodopsin mislocalization, maintains nearly normalappearing rod outer segments, and prevents photoreceptor death in the Bbs4-null mouse model. Analysis of the electroretinogram awave indicates that rescued rod cells are functionally indistinguishable from wild-type rods. These results demonstrate that gene therapy can prevent retinal degeneration in a mammalian BBS model. ciliopathies | intra-flagellar transport | electroretinography B ardet-Biedl syndrome (BBS) is clinically diagnosed by the presence of at least four of the following signs: retinal dystrophy, polydactyly, obesity, learning disabilities, male hypogonadism, and renal anomalies (1). Of these, the visual phenotype is particularly devastating: the average BBS patient will progress to legal blindness before his or her 16th birthday. There are currently 15 genetic loci (Online Mendelian Inheritance in Man #209900) that are known to be associated with BBS, and although inheritance of this disease was once thought to follow a classic autosomal recessive pattern, recent evidence suggests that a more complex pattern, termed "triallelic inheritance," is involved at certain BBS loci (2). Only within the last decade has evidence emerged that BBS proteins play a role in ciliary function (3). More specifically, Bbs4 and the other BBSome components seem to be involved in both recruitment of cargo toward the ciliary basal body (4, 5) and in intraflagellar transport along the cilium (5-7). Several reports have elucidated the mechanisms by which disruption of BBS proteins give rise to the individual phenotypes seen in this highly pleiotropic syndrome (8-11).Retinal degeneration is a central feature of all BBS mouse models generated to date (8,(12)(13)(14)(15)(16). In rod and cone photoreceptors, the connecting cilium is a highly specialized ciliary structure that serves as the sole conduit from the inner segment to the outer segment. Because protein synthesis occurs proximal to the outer segment, rhodopsin and other visual proteins must be trafficked through the connecting cilium to reach their site of action in the outer segment. Abd-El-Barr et al. (11) showed that when Bbs4 was deleted in mice, rhodopsin and cone opsins became grossly mislocalized in rod and cone photoreceptors, respectively. This was followed by apoptotic photoreceptor death and deterioration of the electroretinogram (ERG) a-and b-waves (14). Ultrastructural analysis of rods from young animals revealed normal-appearing connecting cilia and basal body structures. This latter finding has important implications for gene therapy: because the structural transport apparatus seems to develop normally in Bbs4-nu...