Figure 1. Contribution of the 12 known BBS genes to Bardet-Biedl syndrome. Representative graph of the percentage contribution of each known BBS gene to BBS cases. Families with three mutations in two BBS genes were assigned to the primary locus (the BBS locus with two mutant alleles). Modified from Katsanis, 2004.

Figure 2. Two pedigrees showing the autosomal recessive inheritance pattern of BBS. (a) Pedigree of a consanguineous family, in which the unaffected parents are both carriers of a nonsense mutation in BBS5. Three of the five children are homozygous for the mutant allele and, therefore, affected. Their heterozygous siblings are unaffected (adapted from Li et al., 2004, reproduced by permission from Cell). (b) An autosomal recessive pedigree showing allelic heterogeneity. Two unaffected parents bear two different frameshift mutations in BBS10, respectively. The son bearing both mutant alleles in the same gene are affected (Stoetzel et al., 2006).

Figure 3. Differences in penetrance. (a) Both siblings (asterisks) inherited two mutations in BBS2 from their unaffected parents. However, only one sibling is affected with the disease, challenging the autosomal recessive model. (b) The difference can be explained by the presence of a third mutant allele in BBS6. The sibling bearing a nonsense mutant allele of BBS6 is affected, whereas the sibling that is homozygous wildtype for BBS6 is unaffected, supporting a digenic and triallelic model of inheritance (adapted from Katsanis et al., 2001, reproduced by permission from Science).

Figure 4. Differences in expressivity. (a) In two siblings bearing the same BBS1 genotype, the phenotypes differ in severity. One sibling has only mild mental retardation, whereas the second suffers from severe mental retardation in addition to obesity, delayed speech development and other developmental abnormalities. (b) The difference can be explained by the presence of a third mutant allele in BBS6, consistent with a triallelic model. (c) Another family bearing BBS1 mutations had three affected siblings with the same BBS1 genotype. Two siblings developed early onset severe retinitis pigmentosa, whereas the third only developed a mild form of night blindness later in life. (d) Analysis of the BBS2 genotype explains the difference; the severely affected siblings both bear a third mutation in BBS2, whereas the more mildly affected sibling is wildtype (adapted from Badano et al., 2003a, reproduced by permission from Human Molecular Genetics; adapted from Katsanis, 2004, reproduced by permission from Human Molecular Genetics).

Figure 5. BBS4 in microtubule network organization. (a) BBS4 interacts with PCM1 and PCM1-associated cargo to localize to the centriolar satellites. This function is most likely as a result of its interaction with the p150 subunit of dynactin. (b) If BBS4 function is absent or aberrant, PCM1 does not localize properly to the centriolar satellites, resulting in microtubule network disorganization. (c) A BBS4 dominant negative mutation results in binding of PCM1 and cargo, but inefficient loading of p150, resulting in mislocalization and microtubule disorganization defects (adapted from Kim et al., 2004, reproduced by permission from Nature Genetics).