Mutations in IFT172 cause isolated and syndromic retinal degeneration

Abstract

Purpose: Mutations in genes coding ciliary proteins lead to rare genetic disorders that may affect one or more of the following organs: retina, central nervous system, olfactory epithelium, heart, liver, kidney, skeletal system, gonads and adipose tissue. The purpose of this study was to identify and characterize a new genetic cause of retinitis pigmentosa (RP) with Bardet-Biedl syndrome related features and isolated inherited retinal degeneration (IRD) in three families.

Methods: The families were recruited in different clinical centers in the USA, France and the Netherlands. Patients underwent a full ophthalmic examination and consented to the genetic studies. The affected family members were excluded for mutations in the known genes through various methods involving targeted exome capture, homozygosity mapping and Sanger sequencing. The affected and the unaffected family members were subsequently studied through whole exome sequencing. The identified variants were Sanger validated and further functional studies were performed in ciliated cell lines (mIMCD3), rat retinae and zebrafish. Splicing mutations were studied with a mini-gene assay.

Results: Mutations in IFT172 [Intraflagellar Transport 172 Homolog (Chlamydomonas)] were found to be the likely cause of the disease in the three studied families. The American Bardet Biedl family with two affected sisters carried a missense (c.4701C>A, p.H1567Q) and a splice site mutation (c.1525-1G>A). The Dutch RP patient was compound heterozygous for a missense (c.770T>C, p.L257P) and a putative splice site mutation (c.3112-5T>A), whereas the French RP patient carried a homozygous missense mutation (c.4815T>G, p.D1605E) close to the exon-intron boundary, which may also affect IFT172 splicing. The pathophysiological analyses of the missense and splice site mutations are underway and the results from in vitro and in vivo experiments will be presented.

Conclusions: Mutations in IFT172 cause retinal degeneration with possible syndromic features. The phenotypes may range from severe skeleto-renal disorders (Halbritter et al. AJHG 2013) to isolated IRD. This large phenotypic spectrum may be the result of different primary disease-causing mutations in IFT172 or epistatic effects of variants in other genes.

Keywords: 539 genetics • 696 retinal degenerations: hereditary • 695 retinal degenerations: cell biology