Bi-Allelic PRKCZ Loss-of-Function Variants and Adult-Onset Retinitis Pigmentosa

PRKCZ

Biallelic inactivating PRKCZ variants selectively affecting the long transcript encoding the PB1 domain, with loss of the long isoform, impaired ciliogenesis and altered mitochondrial organization

Among approximately 4500 individuals with unsolved retinal disease recruited through international research and diagnostic programs, 6 biallelic PRKCZ variants were identified in 13 individuals from 10 unrelated families; 5 of these variants are predicted to cause loss of function (frameshift, nonsense or splice-altering). Most patients carry a recurrent frameshift variant, c.139_140del (p.Met47ValfsTer19), and all variants selectively affect the long PRKCZ transcript encoding the PB1 domain. The phenotype is adult-onset retinitis pigmentosa (18 to 49 years): progressive night blindness, peripheral visual field constriction and eventual central vision loss; four individuals have adult-onset sensorineural hearing loss. Patient fibroblasts show selective loss of the long isoform, impaired ciliogenesis and altered mitochondrial organization, validated in stable knockdown cell lines; the missense variant disrupts PB1 domain-mediated protein interactions.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A new gene for adult-onset recessive retinitis pigmentosa, already covered by exome and genome sequencing: the interpretation point is the isoform-specific mechanism, which requires taking into account the long retinal transcript, the only one affected by the reported variants. The recurrent frameshift is the first variant to look for in unsolved retinitis pigmentosa. The contribution remains rare (10 families out of about 4500 individuals tested), and the hearing loss seen in four patients needs to be clarified in other series.

Analysis by Dr Thibaut Benquey