BBS is also a good example for our current understanding of genetic and functional ciliary cell biology. The BBS phenotype can be caused by a variety of genes. Mutations in 20 genes have currently been described as the cause of BBS [
6], which may initially seem to be a surprisingly high number. Still, the observation that a large group of the affected gene products form a joint “BBSome”-protein complex [
17] makes it easier to understand that mutations in so many different genes result in the same phenotype. This landmark finding strongly suggests that the overlapping phenotypical and clinical presentation of mutations is directly linked to a common cellular function of the affected gene products within the cell.
According to our current understanding, the phenotype of a ciliopathy patient can therefore be regulated by the genotype in multiple ways. While it is obviously important which gene is affected by a mutation, the phenotype may also change according to the type of mutation,
i.e., missense mutation vs. truncating mutation. A good example are the different subtypes of mutations in the
CEP290 gene, which can either result in isolated nephronophthisis, in the more severe Joubert syndrome, or in the most severe, often embryonic lethal Meckel-Gruber syndrome [
6]. Comparable reports have been described for other ciliopathy genes. For
NPHP3, the phenotypic variability can be explained by the type of mutation with biallelic missense mutations resulting in the less severe phenotype of isolated nephronophthisis and two truncating mutations resulting in a Meckel-Gruber phenotype [
18]. In addition to the type of mutation and the affected gene, the concept of “mutational load” with evidence of genetic interaction of different ciliopathy genes, has received much attention [
1,
6]. Various cilia-associated disorders show more severe phenotypes in patients with additional modifying mutations in functionally related ciliary genes as seen in patients with homozygous
NPHP1 deletions, in whom,
e.g., additional
NPHP6 mutations could be detected in patients with a more severe neurological phenotype [
19]. Finally, some genetic alterations
per se may also not lead to the clinical phenotype but only become clinically relevant in patients with other mutations in ciliary genes. Combined heterozygous mutations in two autosomal recessive genes might therefore result in truly “oligogenic” inheritance [
1,
2,
6], as suggested for Bardet-Biedl syndrome [
20].
Overall, a concept emerges according to which the amount and severity of mutations in functionally related genes are crucial for the clinical phenotype. As different ciliopathy protein complexes can be found in different subcompartments of this cellular organelle, such a concept includes the possibility of differential phenotypes according to the different affected subparts of the cilium.