OFD Type I syndrome: lessons learned from a rare ciliopathy

Abstract

The OFD1 gene was initially identified as the gene responsible for the X-linked dominant male lethal OFD type I syndrome, a developmental disorder ascribed to cilia disfunction. The transcript has been subsequently associated to four different X-linked recessive conditions, namely Joubert syndrome, retinitis pigmentosa, primary ciliary dyskinesia and Simpson-Golabi-Behmel type 2 syndrome. The centrosomal/basal body OFD1 protein has indeed been shown to be required for primary cilia formation and left-right asymmetry. The protein is also involved in other tasks, e.g. regulation of cellular protein content, constrain of the centriolar length, chromatin remodeling at DNA double strand breaks, control of protein quality balance and cell cycle progression, which might be mediated by non-ciliary activities. OFD1 represents a paradigmatic model of a protein that performs its diverse actions according to the cell needs and depending on the subcellular localization, the cell type/tissue and other possible factors still to be determined. An increased number of multitask protein, such as OFD1, may represent a partial explanation to human complexity, as compared with less complex organisms with an equal or slightly lower number of proteins.

Keywords: OFD1; cilia; pleiotropic protein; rare diseases.