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. 2017 Mar-Apr;38(2):127-132.
doi: 10.3109/13816810.2016.1151898. Epub 2016 Mar 30.

Putative digenic inheritance of heterozygous RP1L1 and C2orf71 null mutations in syndromic retinal dystrophy

Yangfan P Liu  1 , Daniëlle G M Bosch  2   3   4   5 , Anna M Siemiatkowska  3   4 , Nanna Dahl Rendtorff  6   7 , F Nienke Boonstra  2   5 , Claes Möller  8 , Lisbeth Tranebjærg  6   7 , Nicholas Katsanis  1 , Frans P M Cremers  3   4   5
Affiliations

Putative digenic inheritance of heterozygous RP1L1 and C2orf71 null mutations in syndromic retinal dystrophy

Yangfan P Liu et al. Ophthalmic Genet. 2017 Mar-Apr.

Abstract

Background: Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration and can occur in non-syndromic and syndromic forms. Syndromic RP is accompanied by other symptoms such as intellectual disability, hearing loss, or congenital abnormalities. Both forms are known to exhibit complex genetic interactions that can modulate the penetrance and expressivity of the phenotype.

Materials and methods: In an individual with atypical RP, hearing loss, ataxia and cerebellar atrophy, whole exome sequencing was performed. The candidate pathogenic variants were tested by developing an in vivo zebrafish model and assaying for retinal and cerebellar integrity.

Results: Exome sequencing revealed a complex heterozygous protein-truncating mutation in RP1L1, p.[(Lys111Glnfs*27; Gln2373*)], and a heterozygous nonsense mutation in C2orf71, p.(Ser512*). Mutations in both genes have previously been implicated in autosomal recessive non-syndromic RP, raising the possibility of a digenic model in this family. Functional testing in a zebrafish model for two key phenotypes of the affected person showed that the combinatorial suppression of rp1l1 and c2orf71l induced discrete pathology in terms of reduction of eye size with concomitant loss of rhodopsin in the photoreceptors, and disorganization of the cerebellum.

Conclusions: We propose that the combination of heterozygous loss-of-function mutations in these genes drives syndromic retinal dystrophy, likely through the genetic interaction of at least two loci. Haploinsufficiency at each of these loci is insufficient to induce overt pathology.

Keywords: Cerebellum; ciliopathy; digenic inheritance; hearing loss; retinitis pigmentosa; zebrafish.

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Conflict of interest statement

DECLARATION OF INTEREST

The authors report no conflicts of interest.

Figures

Fig. 1
Fig. 1. Clinical and genetic characterization of a family with syndromic retinal dystrophy
(A, B) Fundus photographs (A = right eye, B = left eye) taken at 18 years of age show normal retinal vessels, maculae with small wall-shaped degenerative changes and pale optic discs in both eyes. (C) Pedigree of the family. The arrow indicates the person in whom exome sequencing was performed. (D) Validation by Sanger sequencing of the identified RP1L1 c.[326_327insT;7117C>T] and C2orf71 c.1535C>A mutations in the affected individual, the unaffected sibling and her parents. Segregation analyses by Sanger sequencing point towards a digenic inheritance. As = antisense, M = mutation, s = sense, WT = wild-type.
Fig. 2
Fig. 2. Genetic interaction between rp1l1 and c2orf71l in zebrafish
(A) Convergent extension defects were observed in 10 somites stage (ss) embryos injected with a splice-blocking (SB) morpholino oligonucleotide (MO) against rp1l1 and/or a translation blocking (TB) MO against c2orf71l. Lateral view is shown in upper panels, with body gap angles marked by blue dashed lines; dorsal view is shown in lower panels. (B) Proportion of embryos in (A) shows additive effect between rp1l1 and c2orf71l on convergent extension defects. Fisher exact test results were shown with * indicating p<0.05, and *** indicating p<0.001. (C) In the first row, the size of the eye (marked with blue dashed lines) in 5 days post fertilization (dpf) larvae was measured in lateral view. In the second row, cryosections of 5 dpf larva eyes were stained with anti-rhodopsin (zpr-3, green) and nuclear counterstain DAPI (blue). The green channel of delineated areas in second row was shown in the third row. (D) B-box plot of relative eye size (as marked in first row of (C)) was plotted, percent decrease of median compared to control was shown, suggesting additive effect between rp1l1 and c2orf71l on eye size phenotype. Two-tail t-test results were shown with *** indicating p<0.001. (E) Dorsal view (anterior end pointing up) of the heads of 5 dpf embryos stained with acetylated-tubulin antibody, showing mild and severe defects in cerebellum (marked with blue dashed lines) induced by injection of rp1l1 SB and/or c2orf71 TB. (F) Proportion of embryos with mild and severe cerebellum defects shown in (E) was plotted, suggesting synergistic effect between rp1l1 and c2orf71 on cerebellum defects. Fisher exact test results were shown with * indicating p<0.05, and *** indicating p<0.001.
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