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New disease loci
Original article
Missense mutations in the WD40 domain of AHI1 cause non-syndromic retinitis pigmentosa
  1. Thanh-Minh T Nguyen1,2,
  2. Sarah Hull3,4,
  3. Ronald Roepman1,2,
  4. L Ingeborgh van den Born5,
  5. Machteld M Oud1,2,
  6. Erik de Vrieze6,7,
  7. Lisette Hetterschijt6,7,
  8. Stef J F Letteboer1,2,
  9. Sylvia E C van Beersum1,2,
  10. Ellen A Blokland1,
  11. Helger G Yntema1,
  12. Frans P M Cremers1,7,
  13. Paul A van der Zwaag8,
  14. Gavin Arno3,4,
  15. Erwin van Wijk6,7,
  16. Andrew R Webster3,4,
  17. Lonneke Haer-Wigman1,7
  1. 1 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
  2. 2 Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
  3. 3 UniversityCollege London, Instituteof Ophthalmology, London, United Kingdom
  4. 4 Moorfields Eye Hospital, London, United Kingdom
  5. 5 The Rotterdam Eye Hospital, Rotterdam, The Netherlands
  6. 6 Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands
  7. 7 Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands
  8. 8 Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  1. Correspondence to Lonneke Haer-Wigman, Department of Human Genetics, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands; lonneke.haer-wigman{at}radboudumc.nl

Abstract

Background Recent findings suggesting that Abelson helper integration site 1 (AHI1) is involved in non-syndromic retinal disease have been debated, as the functional significance of identified missense variants was uncertain. We assessed whether AHI1 variants cause non-syndromic retinitis pigmentosa (RP).

Methods Exome sequencing was performed in three probands with RP. The effects of the identified missense variants in AHI1 were predicted by three-dimensional structure homology modelling. Ciliary parameters were evaluated in patient’s fibroblasts, and recombinant mutant proteins were expressed in ciliated retinal pigmented epithelium cells.

Results In the three patients with RP, three sets of compound heterozygous variants were detected in AHI1 (c.2174G>A; p.Trp725* and c.2258A>T; p.Asp753Val, c.660delC; p.Ser221Glnfs*10 and c.2090C>T; p.Pro697Leu, c.2087A>G; p.His696Arg and c.2429C>T; p.Pro810Leu). All four missense variants were present in the conserved WD40 domain of Jouberin, the ciliary protein encoded by AHI1, with variable predicted implications for the domain structure. No significant changes in the percentage of ciliated cells, nor in cilium length or intraflagellar transport were detected. However, expression of mutant recombinant Jouberin in ciliated cells showed a significantly decreased enrichment at the ciliary base.

Conclusions This report confirms that mutations in AHI1 can underlie autosomal recessive RP. Moreover, it structurally and functionally validates the effect of the RP-associated AHI1 variants on protein function, thus proposing a new genotype–phenotype correlation for AHI1 mutation associated retinal ciliopathies.

  • AHI1
  • Jouberin
  • WD40 domain
  • non-syndromic retinitis pigmentosa
  • exome sequencing

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/jmedgenet-2016-104200

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    Footnotes

    • Contributors T-MTN performed AHI1 transfection experiments and immunohistochemistry; T-MTN, LH and EdV performed zebrafisch knock-down and analysis of zebrafish sequence; SH, LIvdB and PAvdZ collected clinical cases and performed clinical examinations of patients; MMO and T-MTN performed fibroblast evaluations; SJL performed yeast-2-hybrid analysis; SEB performed TAP analysis; SH, EAB and LH-W performed Sanger sequencing; HY, GA and LH-W analyzed the exome data; LH-W performed modeling of the AHI1 variants in the WD-40 domain; RR, FPMC, EvW, ARW and LH-W designed the study; T-MTN, SH, RR, ARW and LH-W wrote the manuscript.

    • Funding This work was supported by research grants from the Rotterdamse Stichting Blindenbelangen (to EV, FPMC, EW and LH-W), Stichting Blindenhulp (to EV, FPMC, EW and LH-W), Stichting tot Verbetering van het Lot der Blinden (to EV, FPMC, EW and LH-W), Stichting voor Ooglijders (to EV, FPMC, EW and LH-W), the European Community’s Seventh Framework Programmes FP7/2009 under grant agreement no: 241955 (SYSCILIA) to RR, by the Netherlands Organization for Scientific Research (NWO Vici-865.12.005) to RR, and by the Foundation Fighting Blindness (C-CMM-0811-0546-RAD02) to RR.

    • Competing interests None declared.

    • Patient consent The patients of this study already signed internal Radboudumc and Univeristy College of London informed consent forms that were specifically designed to consent for exome sequencing and publishment of results.

    • Ethics approval Institutional review board Radboudumc and institutional review board University College London.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Correction notice This paper has been updated since it first published online. Funding information have been added.