Whole-exome sequencing reveals POC5 as a novel gene associated with autosomal recessive retinitis pigmentosa

Abstract

Retinitis pigmentosa (RP), the most common form of inherited retinal degeneration, is associated with different groups of genes, including those encoding proteins involved in centriole and cilium biogenesis. Exome sequencing revealed a homozygous nonsense mutation [c.304_305delGA (p. D102*)] in POC5, encoding the Proteome Of Centriole 5 protein, in a patient with RP, short stature, microcephaly and recurrent glomerulonephritis. The POC5 gene is ubiquitously expressed, and immunohistochemistry revealed a distinct POC5 localization at the photoreceptor connecting cilium. Morpholino-oligonucleotide-induced knockdown of poc5 translation in zebrafish resulted in decreased length of photoreceptor outer segments and a decreased visual motor response, a measurement of retinal function. These phenotypes could be rescued by wild-type human POC5 mRNA. These findings demonstrate that Poc5 is important for normal retinal development and function. Altogether, this study presents POC5 as a novel gene involved autosomal recessively inherited RP, and strengthens the hypothesis that mutations in centriolar proteins are important cause of retinal dystrophies.

Adolescent idiopathic scoliosis associated POC5 mutation impairs cell cycle, cilia length and centrosome protein interactions

“…It is also involved in cell functions such as cell polarity, division, motility, and forms part of the cell cytoskeleton that is important for cell dynamics [7–9]. The localization of POC5 within photoreceptors is crucial for ciliary connection and retinal function [10].…”

TetrahymenaPoc5 is a transient basal body component that is important for basal body maturation

“…Similarly, flagella are frequently absent in centrin-depleted Chlamydomonas cells as a result of delayed BB development and improper BB maturation (Koblenz et al, 2003). Notably, this role for Poc5 in BB maturation may provide a functional explanation for ciliary defects associated with hPOC5 mutations, including shorter cilia observed with overexpression of a hPOC5 variant associated with adolescent idiopathic scoliosis (Hassan et al, 2019; Patten et al, 2015; Weisz Hubshman et al, 2018; Xu et al, 2018). Also, Poc5 and centrin colocalize in the connecting cilium of photoreceptors, which corresponds structurally to the TZ and is vital for retinal function (Weisz Hubshman et al, 2018; Wheway et al, 2014; Ying et al, 2019).…”

“…This role for hPOC5 is notable because molecular mechanisms that contribute to building a full-length centriole/BB remain poorly understood, especially compared with the mechanistic and molecular understanding of early assembly (Chang et al, 2016; Chen et al, 2017; Comartin et al, 2013; Keller et al, 2009; Schmidt et al, 2009). Furthermore, a truncating mutation in hPOC5 was recently implicated in an inherited form of retinal degeneration, retinitis pigmentosa, characterized by progressive loss of photoreceptors, and Poc5 was found to colocalize with centrin in the connecting cilium of zebrafish photoreceptors, where it is important for normal retinal development and function (Weisz Hubshman et al, 2018; Wheway et al, 2014). Additionally, hPOC5 mutations associated with adolescent idiopathic scoliosis lead to mislocalization of hPOC5, impaired cell cycle progression, and shorter cilia (Hassan et al, 2019).…”

The High-Throughput Analyses Era: Are We Ready for the Data Struggle?

“…These techniques have impacted every field of molecular research, escalating previously used sequencing technologies [ 11 ], and opening the way to the -omic sciences foundation [ 1 , 2 ]. Indeed, NGS methods allow the sequencing of entire genomes [ 12 , 13 , 14 , 15 ], of exomes [ 16 , 17 , 18 ], of panels of genes related to a disease of interest [ 19 , 20 , 21 ], or of a single gene [ 22 , 23 , 24 , 25 , 26 ], but can also be used to explore the entire transcriptome [ 27 , 28 , 29 ], small RNAs [ 30 , 31 , 32 ], the epigenome [ 33 , 34 ], and the microbiome [ 35 , 36 , 37 , 38 ].…”

“…In this view, it is not surprising that NGS is also becoming a reference method for molecular diagnostics [ 10 ]. In particular, NGS allows not only the analysis, in more patients simultaneously, of disease-related genes in less time and at lower costs than traditional approaches, but also the sequencing of panels of genes up to the complete exome [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. In this way, it is possible to increase the diagnostic sensitivity, to discover novel disease-related genes and also obtain data regarding other genes that were potentially acting as disease-phenotype modifiers [ 19 , 40 , 41 , 42 ].…”