Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome

Abstract

Bardet-Biedl syndrome (BBS, OMIM 209900) is a genetic disorder with the primary features of obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation and hypogenitalism. Individuals with BBS are also at increased risk for diabetes mellitus, hypertension and congenital heart disease. What was once thought to be a homogeneous autosomal recessive disorder is now known to map to at least six loci: 11q13 (BBS1), 16q21 (BBS2), 3p13 p12 (BBS3), 15q22.3 q23 (BBS4), 2q31 (BBS5) and 20p12 (BBS6). There has been considerable interest in identifying the genes that underlie BBS, because some components of the phenotype are common. Cases of BBS mapping ro BBS6 are caused by mutations in MKKS; mutations in this gene also cause McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly and congenital heart defects). In addition, we recently used positional cloning to identify the genes underlying BBS2 (ref. 16) and BBS4 (ref. 17). The BBS6 protein has similarity to a Thermoplasma acidophilum chaperonin, whereas BBS2 and BBS4 have no significant similarity to chaperonins. It has recently been suggested that three mutated alleles (two at one locus, and a third at a second locus) may be required for manifestation of BBS (triallelic inheritance). Here we report the identification of the gene BBS1 and show that a missense mutation of this gene is a frequent cause of BBS. In addition, we provide data showing that this common mutation is not involved in triallelic inheritance.

Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse

“…Loss of function of either BBS protein affected the olfactory, but not the respiratory, epithelium, causing severe reduction of the ciliated border, disorganization of the dendritic microtubule network and trapping of olfactory ciliary proteins in dendrites and cell bodies. Our data indicate that BBS proteins have a role in the microtubule organization of mammalian ciliated cells and that anosmia might be a useful determinant of other pleiotropic disorders with a suspected ciliary involvement.BBS is caused by mutations in at least eight loci, seven of which have been identified 6,[8][9][10][11][12][13][14] . Although the sequences of the BBS proteins have not provided any clues to their function, BBS4, BBS5 and BBS8 are localized to the basal body of cultured cells and at ciliated borders in tissues 6,7,10 .…”

“…BBS is caused by mutations in at least eight loci, seven of which have been identified 6,[8][9][10][11][12][13][14] . Although the sequences of the BBS proteins have not provided any clues to their function, BBS4, BBS5 and BBS8 are localized to the basal body of cultured cells and at ciliated borders in tissues 6,7,10 .…”

“…Seven of these 19 individuals (37%) had scores in the range of 3-7, and another two individuals (10%) had intermediate scores (Supplementary Table 1 online). Notably, four of the six individuals who were homozygous with respect to a mutation causing the amino acid substitution M390R in BBS1, the most common BBS-associated mutation in individuals of European descent 13,17 , had scores in the normal range. This result is consistent with the hypothesis that mutations in additional loci can modify the expressivity of the phenotype 10,17,18 .…”

Syndrome de Bardet-Biedl : cils et obésité

“…En effet, les ciliopathies [12] se traduisent cliniquement par un large spectre d'atteintes, pouvant toucher soit un seul organe, la rétine, dans le cas de l'amaurose congénitale de Leber, soit plusieurs organes, par exemple dans les syndromes de BardetBiedl (BBS ; MIM : 209900) et d'Alström (ALMS ; MIM : 203800) ; BBS et ALMS, bien que divergeant quant à la survenue d'un diabète, sont les deux principales ciliopathies souvent associées à une obésité morbide. À ce jour, le BBS est l'une des ciliopathies les plus étudiées avec 19 gènes identifiés (BBS1-19) [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] tandis que le syndrome d'Alström n'a été associé qu'à un seul gène (ALMS1) [32]. À l'instar de nombreuses maladies génétiques rares, on constate un vif intérêt pour l'étude de ces ciliopathies qui, en associant de facto un gène donné à une pathologie donnée, peuvent faciliter l'étude des mécanismes associés.…”

Análise cromossômica por microarray em pacientes com deficiência intelectual associada à obesidade

“…Dezoito genes já foram relacionados à síndrome (17), além de uma forma trialélica, envolvendo um terceiro alelo mutado em um segundo locus (18). Estima-se que sua frequência seja de 1/125.000 a 1/175.000 (6).…”