OFD1: One gene, several disorders

Abstract

The OFD1 protein is necessary for the formation of primary cilia and left-right asymmetry establishment but additional functions have also been ascribed to this multitask protein. When mutated, this protein results in a variety of phenotypes ranging from multiorgan involvement, such as OFD type I (OFDI) and Joubert syndromes (JBS10), and Primary ciliary dyskinesia (PCD), to the engagement of single tissues such as in the case of retinitis pigmentosa (RP23). The inheritance pattern of these condition differs from X-linked dominant male-lethal (OFDI) to X-linked recessive (JBS10, PCD, and RP23). Distinctive biological peculiarities of the protein, which can contribute to explain the extreme clinical variability and the genetic mechanisms underlying the different disorders are discussed. The extensive spectrum of clinical manifestations observed in OFD1-mutated patients represents a paradigmatic example of the complexity of genetic diseases. The elucidation of the mechanisms underlying this complexity will expand our comprehension of inherited disorders and will improve the clinical management of patients.

Keywords: OFD1; X inactivation; X-linked Joubert; cilia; primary ciliary dyskinesia; variable expressivity.

FIGURE 1

A schematic representation of the OFD1 gene is shown. Exons and introns are in scale and indicated in black and gray, respectively. The exon’s number is indicated above exons. Colored bars represent the localization of mutations per each disease phenotypes. Yellow bar OFD type I; light blue bar, JBS10; red bars, RP23; green bar, PCD patients. Protein domains are indicated in the coding region and detailed in the scheme. The LIR domain indicated with a red triangle has been experimentally validated (Morleo et al., 2021)

FIGURE 2

Schematic representation of the localization of the nucleotide changes identified in the OFD1 gene in male individuals. The program Protein paint (https://proteinpaint.stjude.org/) was used. Top, RNA length and base pairs are indicated. Bottom, frameshifts, missense, non‐sense, splicing, and indel mutations are reported according to the color code. The domains are shown and indicated following the nomenclature reported. Only the experimentally validated LIR in exon 21 is reported. Exons are represented as rectangles of different size, number within exons indicate positions of aminoacids. Exons, domains, RNA and mutations are in scale. # fetus, @ nucleotide changes nonconvincingly responsible for the phenotype. OFDI, OFD type I; JBS10, X‐linked recessive Joubert syndrome; RP23, retinitis pigmentosa; PCD primary ciliary dyskinesia

FIGURE 3

Comparison between the clinical manifestations observed in OFD type I patients and in the murine model for OFD type I syndrome. The figure illustrates that the phenotype observed in mice is more severe than that observed in humans: newborn Ofd1 ^Δ4–5/+ females die at birth while female patients have normal life expectancy depending on the presence/severity of the cystic disease and the CNS involvement. Concerning the cranio‐facial‐oral abnormalities, these are present in 100% of heterozygous mice analyzed (palatoschisis is marked by white arrows), while patients display an evident phenotypic variability. Examples of this are signs such as facial milia (ear), bifid lobulated tongue, teeth abnormalities and cleft palate. Limb and skeletal abnormalities are also very variable among patients while polydactyly is always present in female mutants as revealed by alizarin red (bone) and alcian blue (cartilage) staining. Cystic kidney is present in about 40% of patients while renal cysts were observed in all mutant animals. Finally cardiovascular abnormalities were observed in most mutant animals analyzed to date, both females and male embryos, while these anomalies have been rarely reported in OFD type I patients (from Morleo & Franco, , with permission)