They identify a potential modifying gene as the cause of a rare cilia disease.
VALENCIA (EP). A team of researchers from CIBERER at the University of Barcelona and the Vall d’Hebron Research Institute (VHIR) studied a family in which several members suffered from X-linked retinitis pigmentosa (XLRP), in which in one of its members it also presented with primary ciliary dyskinesia ( CDS) in order to clarify the reasons for this variability. The research team analyzed a genetic variant that causes retinitis pigmentosa in a family and identified a potential modifying gene that causes PCD.
Ciliopathies are rare diseases in which the formation or function of cilia is impaired. There is high ciliary specialization, from the motile cilia of the respiratory epithelium to the primary cilia necessary for neurodevelopment or the formation of many organs, and the neurosensory cilia of the ear and retina. There are proteins common to several types of cilia, as well as other proteins that are tissue specific, so ciliopathies can be syndromic or nonsyndromic.
Primary ciliary dyskinesia (PCD) is a respiratory ciliopathy that can usually be associated with changes in other tissues with motile cilia. However, in exceptional cases, in some families, ACL can occur together with retinitis pigmentosa.
In turn, mutations in the RPGR gene cause more than 70 percent of cases of X-linked retinitis pigmentosa (XLRP). This gene mediates retinal-specific alternative splicing but also produces a protein isoform expressed in all hair cells.
Family Research
Research team coordinated Nuria Kamats-Tarruella And Gemma Marfanistudied a family with two sons and a mother with X-linked retinitis pigmentosa, in which one of the sons also has PCD.
The study, published in the journal Cells, examined whether and if the missense variant RPGR, potentially causing retinitis pigmentosa in two sons and a mother, could explain PCD in only one of the boys. there could be other gene modifications that explain the phenotypic variation within the family.
Immunofluorescence abrasion of the nasal epithelium of siblings and the carrier mother showed that expression of the mutated allele correlates with less localization of RPGR in the ciliary transition zone and its delocalization in the cytoplasm. This was confirmed by in vitro expression assays.
The search for new variants in a proband with PCS made it possible to identify missense variants in heterozygosity for CEP290, another gene that causes syndromic ciliopathies. The localization of the CEP290 protein in the ciliary transition zone was also affected in patients, linking the RPGR variant to altered transport and localization of ciliary proteins.
These results indicate a functional relationship between both proteins and therefore suggest that CEP290 should also be analyzed as a potential modifier of the respiratory phenotype in families with cases of PCD and XLRP.
The study was carried out in collaboration with the group of the Andalusian Public Foundation Progreso y Salud de Andalucía.