Ciliopathies and Defects of Brain Development

Defects in the function of cellular organelles such as peroxisomes, lysosomes, and mitochondria are well-known causes of human diseases. Recently, another organelle has also been added to this list. Cilia -tiny hair-like organelles attached to the cell surface- are located on almost all polarized cell types of the human body and have been adapted as versatile tools for various cellular functions, explaining why cilia-related disorders can affect many organ systems. Several molecular mechanisms involved in cilia-related disorders have been identified that affect the structure and function of distinct cilia types. Most ciliopathies result from abnormal signaling mechanisms due to dysfunction of nonmotile monocilia. However, motile cilia of ependymal cells lining the brain ventricles and the aqueduct also play a role in hydrocephalus formation. Ciliopathies are an extensive group of autosomal recessive or X-linked disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. Neurological disorders comprise Joubert syndrome (JS), Cogan syndrome, oral-facial-digital syndrome (OFD), Meckel-Gruber syndrome (MKS), Bardet Biedl syndrome (BBS), microcephaly syndrome, acrocallosal syndrome (ACLS) as well as other rare syndromes such as tectocerebellar dysraphia with occipital encephalocele (TCDOE). Nonneurological disease manifestations consist of renal disease (in particular renal cystic disease), eye disease (e.g., retinal dystrophy, Leber congenital amaurosis and coloboma), skeletal disease (e.g., cone-shape epiphyses in Mainzer-Saldino syndrome, thoracic abnormalities in Jeune syndrome, polydactyly), cranioectodermal dysplasia, cardiac disease (laterality defects), liver fibrosis, pancreatic disease, as well as lung disease.