Bardet-Biedl syndrome

Definition: Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive genetic disorder with the primary features of obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism.

Bardet-Biedl syndrome (BBS) is characterised by progressive pigmentary retinopathy, obesity, hypogenitalism, renal involvement (including cysts, renal cortical loss or reduced ability to concentrate urine), mild mental retardation and postaxial polydactyly of the hands and feet.

BBS is genetically heterogeneous with at least 12 loci and 10 genes identified, all involved in ciliary function. Hirschsprung disease has been reported in several BBS cases.

BBS and MKS, although distinct clinically, are allelic forms of the same molecular spectrum (MKS1, MKS3 and CEP290-NPHP6 germline mutations).

Synopsis

 systemic anomalies

• obesity
• situs inversus (17163542, 10602122)

 ocular anomalies

• progressive retinal dystrophy
• rod-cone dystrophy, onset be end of 2nd decade (major)
• retinitis pigmentosa
• strabismus
• cataracts

 craniofacial anomalies

• high arched palate
• dental crowding
• hypodontia
• small tooth roots

 cardiovascular anomalies

• left ventricular hypertrophy
• cardiac malformations

 hepatic fibrosis

• with bile-duct proliferation
• without bile-duct proliferation

 Hirschsprung disease (@<@10%) (10602122)
 hypogonadism (major)
  renal anomalies (major)

• medullary-predominant cystic kidneys

 nephrogenic diabetes insipidus
 diabetes mellitus
 postaxial polydactyly (major)
 brachydactyly

Etiology (Seven loci)

Eight BBS-associated genes have been identified so far by positional cloning. For most of the encoded proteins it was shown that they localize to basal bodies and/or centrosomes.

 BBS1 (11q13) (12524598) (30-40%)
 BBS2 (16q21)
 BBS3 (3p13-p12) (ARL6)

• Using bioinformatic screens for ciliary genes in combination with data from positional cloning, mutations in ADP-ribosylation factor-like 6 (ARL6) were identified as responsible for BBS3.
• ARL6, a small GTPase, is specifically expressed in ciliated cells and undergoes intraflagellar transport.

 BBS4 (15q22.3-q23)

• BBS4 protein, as BBS8, (also known as tetratricopeptide repeat domain 8, TTC8) directly interacts with pericentriolar material 1 (PCM1), a component of the pericentriolar material.
• BBS4 is essential for recruiting proteins to the pericentrosomal matrix, confirming the role of centrosomal function in the pathogenesis of BBS.

 BBS5 (2q31)

• A bioinformatics approach that is based on the ciliary and basal body hypothesis of BBS pathogenesis also helped to identify the BBS5 gene, which encodes a novel protein.

 BBS6 (20p12)
 BBS7 (12567324)
 BBS8
-* BBS8 protein (also known as tetratricopeptide repeat domain 8, TTC8), as BBS4, directly interacts with pericentriolar material 1 (PCM1), a component of the pericentriolar material.

 BBS9
 BBS10
 BBS11
 BBS12 (17160889)

Genetic and mutational analyses have indicated that, in some families, a combination of three mutant alleles at two loci (triallelic inheritance) is necessary for pathogenesis (oligogenic disease transmission).

Most Bardet-Biedl syndrome (BBS) protein orthologues are expressed in basal bodies of motile cilia throughout evolution, including in the flagella of the unicellular organism Chlamydomonas reinhardtii; mutations in these genes lead to defective intraflagellar transport (IFT) or propulsion.

Pathogenesis

 BBS is a pleiotropic disorder that is characterized by retinal degeneration, obesity, learning difficulties and polydactyly, as well as gonadal malformations and renal malformations including cystic kidney diseases (CKDs). These defects are thought to be caused by centrosomal and ciliary dysfunction.

 Thus, the importance of the centrosome and the basal body in orchestrating and possibly regulating cargo trafficking to maintain structural and functional ciliary integrity is highlighted by recent studies in BBS.

In mammalian cell lines, at least two of the eight known BBS proteins, BBS4 and BBS8, localize to centrosomes and basal bodies.

Yeast two-hybrid assays and co-immunoprecipitation in mammalian cells shows that these proteins interact with PCM1, a known component of the pericentriolar satellites.

 In vitro and in vivo studies have demonstrated that BBS4 is required for the correct localization of PCM1 to the pericentriolar satellites and that depletion of BBS4 through RNAi leads to microtubule network disorganization.

 Consistent with a role of the BBS proteins (BBSs) in centrosome/basal body organization and ciliary function, translational Bbs-Gfp transgenes for bbs-1, bbs-2, bbs-7 and bbs-8 show specific signals at the ciliary transition zones (basal bodies) and axonemes, BBS-GFP fusion proteins undergo IFT, and loss of function of bbs-7 and bbs-8 leads to shortened cilia and defective IFT of some IFT proteins.

For example, loss of BBS-7 and BBS-8 in Caenorhabditis elegans causes defective IFT of OSM-5 and CHE-11 - proteins that are involved in osmotic avoidance and chemotaxis respectively.

 Similarly to inversin (INVS), some of the BBS proteins could also provide a functional link between cilia and the interior of the cell.

 BBS8 shows limited similarity to the budding yeast cdc23 protein, a member of the APC, although the biological relevance of these findings needs further evaluation.

 BBS3 is a member of the ARF family of small GTP-binding proteins that regulate vesicle trafficking. In C. elegans, BBS-3 localizes to the cytoplasm, transition zone (basal body) and cilia of ciliated sensory neurons and undergoes IFT, thereby offering a possible direct link between axonemal and cytoplasmic transport of specific cargo.

See also

 ciliopathies

Reviews

 Hildebrandt F, Otto E. Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease? Nat Rev Genet. 2005 Dec;6(12):928-40. PMID: 16341073

 Badano JL, Teslovich TM, Katsanis N. The centrosome in human genetic disease. Nat Rev Genet. 2005 Mar;6(3):194-205. PMID: 15738963

 Beales PL. Lifting the lid on Pandora’s box: the Bardet-Biedl syndrome. Curr Opin Genet Dev. 2005 Jun;15(3):315-23. PMID: 15917208

 Katsanis N. The oligogenic properties of Bardet-Biedl syndrome. Hum Mol Genet. 2004 Apr 1;13 Spec No 1:R65-71. Epub 2004 Feb 19. PMID: 14976158

 Mykytyn K, Sheffield VC. Establishing a connection between cilia and Bardet-Biedl Syndrome. Trends Mol Med. 2004 Mar;10(3):106-9. PMID: 15106604

 Katsanis N, Lupski JR, Beales PL. Exploring the molecular basis of Bardet-Biedl syndrome. Hum Mol Genet. 2001 Oct 1;10(20):2293-9. PMID: 11673413

References

 Leitch CC, Zaghloul NA, Davis EE, Stoetzel C, Diaz-Font A, Rix S, Al-Fadhel M, Lewis RA, Eyaid W, Banin E, Dollfus H, Beales PL, Badano JL, Katsanis N. Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat Genet. 2008 Apr;40(4):443-8. PMID: 18327255

 Stoetzel C, Muller J, Laurier V, Davis EE, Zaghloul NA, Vicaire S, Jacquelin C, Plewniak F, Leitch CC, Sarda P, Hamel C, de Ravel TJ, Lewis RA, Friederich E, Thibault C, Danse JM, Verloes A, Bonneau D, Katsanis N, Poch O, Mandel JL, Dollfus H. Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome. Am J Hum Genet. 2007 Jan;80(1):1-11. PMID: 17160889

 Ross AJ, May-Simera H, Eichers ER, Kai M, Hill J, Jagger DJ, Leitch CC, Chapple JP, Munro PM, Fisher S, Tan PL, Phillips HM, Leroux MR, Henderson DJ, Murdoch JN, Copp AJ, Eliot MM, Lupski JR, Kemp DT, Dollfus H, Tada M, Katsanis N, Forge A, Beales PL. Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nat Genet. 2005 Oct;37(10):1135-40. PMID: 16170314

 Karmous-Benailly H, Martinovic J, Gubler MC, Sirot Y, Clech L, Ozilou C, Auge J, Brahimi N, Etchevers H, Detrait E, Esculpavit C, Audollent S, Goudefroye G, Gonzales M, Tantau J, Loget P, Joubert M, Gaillard D, Jeanne-Pasquier C, Delezoide AL, Peter MO, Plessis G, Simon-Bouy B, Dollfus H, Le Merrer M, Munnich A, Encha-Razavi F, Vekemans M, Attie-Bitach T. Antenatal presentation of bardet-biedl syndrome may mimic meckel syndrome. Am J Hum Genet. 2005 Mar;76(3):493-504. PMID: 15666242