Human Molecular Genetics, 2001, Vol. 10, No. 20 2293-2299
© 2001 Oxford University Press
Exploring the molecular basis of Bardet–Biedl syndrome
1Departments of Molecular and Human Genetics and 2Department of Pediatrics, 3The Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas, USA and 4Molecular Medicine Unit, Institute of Child Health, University College London, London, UK
Received July 19, 2001; Accepted July 30, 2001.
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ABSTRACT |
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 TOP ABSTRACT CLINICAL SYNOPSIS OF BBSGENETICS OF BBSMOLECULAR PATHOGENESIS OF BBSTHE BBS PROTEINSBBS MUTATIONS AND THE...THE ‘NEWFOUNDLAND...THE FUTURENOTE ADDED IN PROOFREFERENCES |
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Few autosomal recessive disorders display the degree of pleiotropism and genetic heterogeneity found in Bardet–Biedl syndrome (BBS), a genetic disorder characterized primarily by retinal dystrophy, obesity, polydactyly, cognitive impairment and gonadal and renal dysgenesis. This relatively rare condition has been reported frequently, but we have only recently begun to appreciate the genetic complexities that give rise to this constellation of clinical findings. During the last 12 months, the first three of at least six BBS genes have been identified, providing us for the first time with the ability to formulate hypotheses regarding the molecular etiology of the disorder. Here we review the key elements of the phenotype and discuss the significance of the discovery of the first three BBS genes on the effort to identify the cellular causes of this syndrome.
Bardet–Biedl syndrome (BBS; MIM 209900) is a multi-system autosomal recessive disorder, characterized by rod–cone dystrophy, dystrophic extremities, central obesity, hypogonadism, learning difficulties and renal dysplasia. Other features of varying frequency include, among others, diabetes mellitus, hepatic fibrosis, reproductive abnormalities, endocrinologic deficiencies, short stature, developmental retardation and speech and behavioral abnormalities. BBS occurs throughout the world with varying frequencies. Prevalence rates in North America and Europe range from 1:140 000 to 1:160 000 livebirths (1–3). However, in Kuwait and Newfoundland the rate is much higher, with an estimated incidence of 1:13 500 and 1:17 500, respectively, postulating a founder effect (4,5).
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CLINICAL SYNOPSIS OF BBS |
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TOPABSTRACTCLINICAL SYNOPSIS OF BBSGENETICS OF BBSMOLECULAR PATHOGENESIS OF BBSTHE BBS PROTEINSBBS MUTATIONS AND THE...THE ‘NEWFOUNDLAND...THE FUTURENOTE ADDED IN PROOFREFERENCES |
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Classification of the clinical manifestations of BBS is complex and ambiguous due to the pronounced phenotypic variability of the disorder. From a review of case reports and our own experience there appears to be as much intrafamilial as interfamilial variation, with no evidence for any race-specific bias or clues about the underlying genotype (1,6). Based on relative prevalence, the clinical phenotype can be divided into major and minor features (Table 1).
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Retinal degeneration
Retinal dystrophy is one of the hallmarks of the disorder, found occasionally in the first decade but present in almost all patients in the second decade (7). The appearance of the fundus does not predict vision and the defect has been described as an atypical pigmentary retinal dystrophy of the photoreceptors with early macular involvement (Fig. 1A) (8–11).
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Obesity
Obesity is the second major feature of BBS (Fig. 1B), with a frequency of 72–96% depending on measurement criteria (3,5,12). Obesity usually begins in childhood and the severity increases with age, with the majority of cases exhibiting symptoms within the first year of life. Distribution of adipose tissue is widespread in childhood but becomes most prominent in the trunk and proximal limbs in adulthood. Although the cause is unknown, abnormalities of both the pituitary and hypothalamus have been postulated (13,14).
Limb abnormalities
The third major feature that is commonly, but not always, found in BBS is post-axial polydactyly (Fig. 1C and D). In addition to polydactyly, other limb deformities have been reported at varying frequencies (12). Of these, brachydactyly (short fingers) of both hands and feet is most common, and is sometimes associated with partial syndactyly (usually between the second and third toes and absent in the parents), fifth finger clinodactyly (incurved finger) and a prominent gap between the first and second toes (so called ‘sandal-gap’).
Cognitive impairment
Mental retardation is a more disputed feature of BBS. Although early studies described decreased IQ as a major feature of BBS, visual acuity had often not been taken into consideration. In Bell’s retrospective study (13), 86% of patients were said to have a mental defect. This finding was verified by Klein and Ammann (3), who reported a high proportion (78%) with mental retardation, and also tried to categorize the severity of impairment into mild, moderate and severe. They concluded that most cases (
55%) showed only ‘mild feeble-mindedness’. Since then, more recent objective IQ tests determined that only a minority of patients are mentally retarded (5).
Hypogenitalism and genital abnormalities
Hypogenitalism is reported more frequently in BBS males than females (3,13). Several affected women have given birth to children but there have only been two reports of affected males fathering children (3,5,12,13,15). The cause is unknown and several case reports provide evidence for primary gonadal failure (5,16), failure of the hypothalamic-pituitary axis (17) or both (18).
In BBS females, genital abnormalities encompass a wide range including hypoplastic fallopian tubes, uterus and ovaries, partial and complete vaginal atresia, absent vaginal orifice and absent urethral orifice (3,5,9,19–23). Some cases of BBS have been misdiagnosed as McKusick–Kauffman syndrome (MKKS; a syndrome characterized by hydrometrocolpos, polydactyly and congenital heart disease) on this basis (24).
Renal dysfunction
Renal dysfunction has only recently been recognized to be a component of the BBS clinical phenotype. Prior to the 1980s, renal malformations in BBS had been reported infrequently (25–27), although a high frequency of structural abnormalities were observed postmortem (Fig. 1E) (19,21). More recent studies have indicated that renal dysplasia can be present without clinical evidence of renal disease, which would explain the underdetection of such features (28,29). In one study, 26/57 patients (46%) had renal structural abnormalities. However, only 5% had functional impairment at the time of assessment (12).
Minor clinical features
In addition to the major diagnostic features of BBS, multiple minor features have also been documented in patients at varying frequencies. These include developmental delay, speech and language deficit, psychosis, facial dysmorphism, variations in height, neurological abnormalities, hearing loss, metabolic and endocrine disturbances including diabetes mellitus, nephrogenic diabetes insipidus, cardiovascular anomalies, disturbances of dentition and liver function, atresia ani and Hirschprung disease (see 12 for a more comprehensive description).
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GENETICS OF BBS |
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TOPABSTRACTCLINICAL SYNOPSIS OF BBSGENETICS OF BBSMOLECULAR PATHOGENESIS OF BBSTHE BBS PROTEINSBBS MUTATIONS AND THE...THE ‘NEWFOUNDLAND...THE FUTURENOTE ADDED IN PROOFREFERENCES |
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The familial inheritance pattern of the phenotype suggests that BBS is a single-gene autosomal recessive disorder. This poses a challenge to explain how the disruption of the function of a single protein can lead to such a diverse phenotype that encompasses both developmental (e.g. polydactyly) and progressive (e.g. retinal dystrophy) defects.
Initial genetic analyses further complicated the BBS model. The relative consistency of the phenotype led to the expectation that the BBS phenotype would map to a single locus. However, linkage studies revealed substantial genetic heterogeneity: six BBS loci have been identified to date, with evidence for at least one additional locus in the human genome (Table 2). The first BBS locus (BBS2) was mapped in 1993 after a genome-wide scan using a large consanguineous Israeli pedigree showed linkage to D16S408 on 16q21 (30). Soon after, a second locus (BBS1) was reported after a genome-wide search using 31 North American outbred families demonstrated that BBS1 and PYGM on 11q13 were linked and that BBS1 was the major BBS locus, as it accounted for 40% of all pedigrees (31). The third and fourth loci (BBS3 and BBS4) were identified on 3p12–13 and 15q23, respectively, by using the pooled sample homozygosity approach in two large consanguineous Bedouin families (32,33). The fifth locus (BBS5) was mapped to 2q31 using homozygosity mapping in a single, large Newfoundland kindred (34), whereas the most recently identified BBS locus (BBS6) was mapped to 20p12 (35), using a cohort of Newfoundland BBS families that had been excluded from the known BBS loci (36). Finally, the presence of a seventh, as yet unmapped, locus was documented by genetically excluding several pedigrees from all known loci (37).
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MOLECULAR PATHOGENESIS OF BBS |
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TOPABSTRACTCLINICAL SYNOPSIS OF BBSGENETICS OF BBSMOLECULAR PATHOGENESIS OF BBSTHE BBS PROTEINSBBS MUTATIONS AND THE...THE ‘NEWFOUNDLAND...THE FUTURENOTE ADDED IN PROOFREFERENCES |
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After several years of intensive positional cloning efforts, the first three BBS genes were identified over the last 12 months. In the absence of physiological or biochemical clues, the identity of these genes has provided the only tools for gaining insight into the molecular basis of the disorder.
The cloning of the gene for MKKS on 20p12 (38) facilitated the identification of the first BBS gene (BBS6). MKKS has some phenotypic overlap with BBS such as polydactyly and hydrometrocolpos. More importantly, several MKKS patients were reported who later developed retinal dystrophy and obesity and were thus re-classified as BBS (24,39). This observation, coupled with the delineation of the BBS6 critical interval to a 1.9 Mb region which included MKKS (35) proved critical, as mutations in MKKS were shown by two independent groups to cause BBS (35,40).
Both BBS2 and BBS4 were identified using classical positional cloning methods, whereby ancestral recombinants were used to refine the critical intervals to a 2 cM region on 16q21 and a 1 cM region on 15q22.3–q23. Analysis of genomic sequence led to the identification of several candidate genes in each region, one of which was ultimately shown to harbor pathogenic mutations in each case (41,42).
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THE BBS PROTEINS |
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TOPABSTRACTCLINICAL SYNOPSIS OF BBSGENETICS OF BBSMOLECULAR PATHOGENESIS OF BBSTHE BBS PROTEINSBBS MUTATIONS AND THE...THE ‘NEWFOUNDLAND...THE FUTURENOTE ADDED IN PROOFREFERENCES |
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Nucleotide and protein homology searches suggest that BBS6/MKKS is similar to archeobacterial chaperonins and the eukaryotic T-complex-related proteins (TCPs). Three-dimensional modeling has also indicated that the protein whose fold best resembles MKKS is the archeal thermosome from Thermoplasma acidophilum (38). Archeal thermosomes and members of the TCP family belong to the type-II class of chaperonins. In contrast to type I chaperonins, which are often associated with conditions of cellular stress (such as heat-shock proteins), the type-II class is implicated in the facilitation of nascent protein folding in an ATP-dependent manner (for reviews see 43–45).
Unlike BBS6, the amino-acid sequence of BBS2 offers no functional insights. Other than a strong conservation across phyla, implying limited tolerance to variation, the primary sequence of BBS2 bears no homology to any known protein, nor does it contain any recognizable motifs (42). Computational modeling of the three-dimensional configuration of BBS2 does predict the presence of a coiled-coil domain near the N-terminus of the protein (unpublished data). This may indicate that BBS2 polymerizes with itself or other proteins (for a recent review of coiled-coil domains see 46). The diverse function of this domain, however, does not provide other functional clues. Coiled-coils have been found in a wide variety of proteins, ranging from cytoskeletal proteins such as 
-keratin (47) and molecular motor proteins such as myosin (48), to pH-dependent switches such as the macrophage scavenger receptor (49) and transcription factors such as the GCN4 leucine zipper (50). Further experiments will be required to establish the physiological role of BBS2 in the cell.
The most recently identified BBS protein, BBS4, belongs to yet another functional class of proteins as it shows significant similarity to O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) from several species (41). O-GlcNAc modifies a large number of nucleocytoplasmic proteins and is thought to play an important role in signaling by determining how a cell responds to extracellular stimuli (51). In addition, BBS4 contains a potential tetratricopeptide repeat motif (TPR) (41). Such structures are thought to mediate protein–protein interactions in a variety of cellular processes (52). It is therefore possible that BBS4 docks with other proteins to glycosylate specific residues in order to either propagate or block signal transduction.
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BBS MUTATIONS AND THE PHENOTYPE |
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TOPABSTRACTCLINICAL SYNOPSIS OF BBSGENETICS OF BBSMOLECULAR PATHOGENESIS OF BBSTHE BBS PROTEINSBBS MUTATIONS AND THE...THE ‘NEWFOUNDLAND...THE FUTURENOTE ADDED IN PROOFREFERENCES |
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Examination of the types and positions of all mutations found in the first three BBS genes provides a critical entry point for understanding the molecular nature of the disease. Many of the BBS2, BBS4 and BBS6 mutations are either frameshifts, missense or splice aberrations (Table 3). For instance, patients have been reported with homozygous or compound heterozygous frameshift BBS mutations (35,40–42); these introduce premature termination codons and will either produce severely truncated protein or, more likely, result in nonsense-mediated RNA decay (53). Nonsense point mutations found in all three BBS genes may have a similar effect (37,41,42 and unpublished data). This suggests that BBS is likely to be the result of the loss of function of any of the three BBS proteins. Whether the loci are inactivated completely or whether some basal protein activity persists remains to be determined.
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It is also unclear whether there is any correlation between the nature of the BBS mutations and the severity of the disease. One might expect that missense mutations would result in a milder phenotype. This may be the case for some BBS2 mutations. For instance, it has been suggested that the homozygous V75G alteration may result in a ‘leaner’ phenotype, compared to the frameshift and splice junction mutations (42), although more families are required to substantiate this observation.
A stronger phenotype–genotype association can be made for some BBS6 mutations, but even then the explanation might not be as simple as proposed initially. The majority of mutations reported in the first BBS6 studies suggested that a total loss of function causes BBS (35,40), whereas milder alleles give rise to MKKS (38). This led to the hypothesis that MKKS is a hypomorphic variant of BBS (35). However, the molecular stratification between the two syndromes is likely to be more complex. First, all but one of the mutations reported in a later study using a large outbred patient cohort were missense alterations (37). Secondly, two mutant alleles associated with MKKS, Y37C and A242S, were also found in BBS patients (35,37), suggesting that it may be the combination of both alleles that determines the severity of the phenotype. Even this hypothesis, however, may prove to be too simplistic. Genetic and mutational data suggest that some cases of BBS may be caused by mutations in more than one locus, as several BBS6 mutations were detected in pedigrees excluded genetically from BBS6 on the basis of haplotype analyses. In at least one instance, the pedigree was haplotype-inferred to map to BBS2 (37). If this observation is substantiated by mutational data, the hypomorphic nature of MKKS may be the result of both the number of inherited mutant alleles and the combinatorial nature of the mutations.
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THE ‘NEWFOUNDLAND PARADOX’ |
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TOPABSTRACTCLINICAL SYNOPSIS OF BBSGENETICS OF BBSMOLECULAR PATHOGENESIS OF BBSTHE BBS PROTEINSBBS MUTATIONS AND THE...THE ‘NEWFOUNDLAND...THE FUTURENOTE ADDED IN PROOFREFERENCES |
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Mutational analyses of all three known BBS loci raises another issue regarding the genetics of the syndrome in Newfoundland, where BBS is encountered frequently (4). The island of Newfoundland was colonized in the 1700s by a few British and Irish families who established small isolated communities along the coast. The limited initial gene pool and the paucity of migration due to geographic isolation are thought to account for the elevated incidence of recessive disorders by virtue of a founder effect (54). Such founder mutations have been shown to exist in Newfoundland for several disorders such as multiple endocrine neoplasia (55), familial adenomatous polyposis (56) and hereditary non-polyposis colorectal cancer (57). Despite the expectation that the high frequency of BBS in the island was also due to a founder mutation, locus heterogeneity has been demonstrated both genetically and through mutational data. Two disease-associated haplotypes have been found in Newfoundland for BBS1 (58 and unpublished data). Two families have been assigned genetically to BBS2 (36); another family has been linked to BBS3 (59), whereas yet another family defined BBS5 (34). Three distinct BBS6 mutations have also been found in Newfoundland pedigrees (35,40). Finally, digenic inheritance is also suspected in one Newfoundland pedigree (37).
This genetic landscape is reminiscent of another recessive, genetically heterogeneous disorder, limb-girdle muscular dystrophy (LGMD). The population of the Indian Ocean island of La Reunion, exhibits a high frequency of LGMD3. Despite the prediction that this was due to a founder effect, multiple disease-associated haplotypes and mutations in Calpain 3 were found. This was termed ‘La Reunion Paradox’ and multigenic inheritance was postulated as one explanation (60). The ‘Newfoundland Paradox’ is even more pronounced in that not only are there multiple mutations in the same gene found in Newfoundland (exemplified by the three different mutations in BBS6), but also multiple loci. As the presence of eight discrete founder mutations is not likely, it is difficult to reconcile these data with the elevated frequency of the disease. Perhaps the key to solving this conundrum will be to consider multigenic inheritance, whereby one ancestral founder mutation behaving as a dominant susceptibility locus may be paired with mutations at the various known BBS loci to cause disease. Since all BBS models are based on a recessive mode of disease transmission, enrichment in the Newfoundland population for a dominant susceptibility founder locus may have escaped detection.
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THE FUTURE |
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TOPABSTRACTCLINICAL SYNOPSIS OF BBSGENETICS OF BBSMOLECULAR PATHOGENESIS OF BBSTHE BBS PROTEINSBBS MUTATIONS AND THE...THE ‘NEWFOUNDLAND...THE FUTURENOTE ADDED IN PROOFREFERENCES |
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Much remains to be learned about both the genetics and the physiological dysfunction in BBS. A minimum of three more BBS genes remain uncloned and several more loci in the human genome are possibly at large. In addition, the question of multiallelic inheritance must be thoroughly investigated, as it will also have a substantial impact on our understanding of the function of the different BBS proteins and their relationship to each other.
Reconciliation of the pleiotropic BBS phenotype with mutations in a single or a combination of genes will remain difficult until the function of the BBS proteins is elucidated. Assuming that BBS6 is a chaperonin, it may be argued that BBS is caused by a number of molecules whose functionality has been compromised due to misfolding. The association of type-II chaperonins and VHL (61,62) is a tantalizing link to the renal aspects of the phenotype. The same is true for -transducin, a substrate of type-II chaperonins (63) whose loss of function leads to photoreceptor degeneration (64).
Formulating functional hypotheses for BBS2 and BBS4 is more difficult, since little is known about these proteins. Are either or both peptides folded or degraded by BBS6? Do they interact with each other? More importantly, if they do participate in signal transduction as suggested by their motifs, what extracellular signal do they transmit and what is the cellular response to this signal? The answers to these and other related questions will provide important new insights into cellular processes critical for a variety of cellular functions such as energy homeostasis and retinal, limb and kidney development.
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NOTE ADDED IN PROOF |
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TOPABSTRACTCLINICAL SYNOPSIS OF BBSGENETICS OF BBSMOLECULAR PATHOGENESIS OF BBSTHE BBS PROTEINSBBS MUTATIONS AND THE...THE ‘NEWFOUNDLAND...THE FUTURENOTE ADDED IN PROOFREFERENCES |
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Mutational analysis of BBS2 and BBS6 has recently substantiated the hypothesis that mutations in more than one BBS may be required for pathogenesis. In a recent study, Katsanis et al. (65) reported the presence of three disease-causing mutations in four BBS pedigrees. One pedigree had two BBS6 mutations and one BBS2 mutation, whereas three pedigrees had two BBS2 mutations and one BBS6 mutation. Furthermore, in one family an unaffected individual had inherited two null BBS2 mutations but was wild-type for BBS6, whereas the affected sib carried a third null mutaiton in BBS6. This lead the authors to propose that for some pedigrees, mutations at two loci are necessary and sufficient for pathogenesis. They also concluded that on the basis of haplotype analyses across the critical intervals of other BBS loci, this ‘triallelic’ mode of inheritance is likely to involve other BBS genes such as BBS1 and BBS4.
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ACKNOWLEDGEMENTS |
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We thank S.Ansley, J.Badano, C.Boerkoel, E.Eichers and D.Stockton for critical evaluation of this manuscript. This work was supported in part by a National Eye Institute, NIH, grant EY12666 (N.K.), the March of Dimes (N.K., J.R.L.), the Foundation Fighting Blindness, USA (J.R.L.), the Wellcome Trust (P.L.B.) and the Birth Defects Foundation (P.L.B.).
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +1 713 798 6873; Fax: +1 713 798 5073; Email: katsanis@bcm.tmc.edu
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REFERENCES |
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TOPABSTRACTCLINICAL SYNOPSIS OF BBSGENETICS OF BBSMOLECULAR PATHOGENESIS OF BBSTHE BBS PROTEINSBBS MUTATIONS AND THE...THE ‘NEWFOUNDLAND...THE FUTURENOTE ADDED IN PROOFREFERENCES |
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