Researchers from the Growth and Development group of the Vall d'Hebron Research Institute (VHIR) and the University of Barcelona belonging to CIBERER, in collaboration with the Andalusian Public Foundation Progreso y Salud de Andalucía group, have studied a family with several members affected by X-linked retinitis pigmentosa (XLRP), in which one of its members also had primary ciliary dyskinesia (PCD), with the aim of finding the causes of this variability. The research team has analysed the genetic variant causing retinitis pigmentosa in the family and has identified a potentially modifying gene causing PCD.

Ciliopathies are rare diseases in which the formation or function of cilia is altered. There is a high degree of ciliary specialisation, from the motile cilia of the respiratory epithelium to primary cilia required in 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, and other proteins that are tissue-specific, so ciliopathies can be either syndromic or non-syndromic. 

Primary ciliary dyskinesia (PCD) is a respiratory ciliopathy that can commonly occur in combination with alterations in other tissues with motile cilia. However, exceptionally, PCD can occur in conjunction with retinitis pigmentosa in a few families. 

Mutations in the RPGR gene cause more than 70% of cases of X-linked retinitis pigmentosa (XLRP). This gene has a retina-specific alternative splicing, but also produces a protein isoform expressed in all hair cells. 

The research team, coordinated by Núria Camats-Tarruella and Gemma Marfany, has studied a family with two sons and a mother affected by X-linked retinitis pigmentosa in which one of the sons is also affected by PCD.

In the research, published in the journal Cells, it was studied whether a missense variant in RPGR, potentially causing retinitis pigmentosa in the two sons and mother, could explain RPGR in only one of the sons and whether there could be other variants in modifier genes that could explain the phenotypic variability in the family.

Immunofluorescence in nasal epithelial scrapings of the siblings and the carrier mother showed that the expression of the mutated allele correlated with a lower localisation of RPGR in the ciliary transition zone and its delocalisation in the cytoplasm. This was corroborated by in vitro expression assays. The search for new variants in the patient with PCD led to the identification of heterozygous missense variants in CEP290, another gene causing syndromic ciliopathy. The localisation of the CEP290 protein in the ciliary transition zone was also affected in patients, linking the RPGR variant to an alteration in the transit and localisation of ciliary proteins. These findings indicate a functional relationship between the two proteins, suggesting that CEP290 should also be analysed as a potential modifier of the respiratory phenotype in cases of families with FAPD and XLRP.

This work has been carried out within the framework of an Intramural Cooperative and Complementary Action (ACCI) of the CIBERER.