2. Academic Validation
  3. A mutation in IFT43 causes non-syndromic recessive retinal degeneration

A mutation in IFT43 causes non-syndromic recessive retinal degeneration

  • Hum Mol Genet. 2017 Dec 1;26(23):4741-4751. doi: 10.1093/hmg/ddx356.
Pooja Biswas 1 2,  Jacque L Duncan 3,  Muhammad Ali 4,  Hiroko Matsui 5,  Muhammad Asif Naeem 6,  Pongali B Raghavendra 2 7,  Kelly A Frazer 5 8,  Heleen H Arts 9,  Sheikh Riazuddin 6 10 11,  Javed Akram 10 11,  J Fielding Hejtmancik 12,  S Amer Riazuddin 4,  Radha Ayyagari 1
Affiliations

Affiliations

  • 1 Shiley Eye Institute, University of California San Diego, La Jolla, CA, USA.
  • 2 School of Biotechnology, REVA University, Bengaluru, Karnataka, India.
  • 3 Department of Ophthalmology, University of California San Francisco, San Francisco, CA, USA.
  • 4 The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 5 Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
  • 6 National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
  • 7 School of Regenerative Medicine, Manipal University, Bangalore, India.
  • 8 Department of Pediatrics, Division of Genome Information Sciences, Rady Children's Hospital, San Diego, CA, USA.
  • 9 Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
  • 10 Allama Iqbal Medical College, University of Health Sciences Lahore, Pakistan.
  • 11 National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
  • 12 Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD, USA.
PMID: 28973684 DOI: 10.1093/hmg/ddx356
Abstract

The aim of this work is to identify the molecular cause of autosomal recessive early onset retinal degeneration in a consanguineous pedigree. Seventeen members of a four-generation Pakistani family were recruited and underwent a detailed ophthalmic examination. Exomes of four affected and two unaffected individuals were sequenced. Variants were filtered using exomeSuite to identify rare potentially pathogenic variants in genes expressed in the retina and/or brain and consistent with the pattern of inheritance. Effect of the variant observed in the gene Intraflagellar Transport Protein 43 (IFT43) was studied by heterologous expression in mIMCD3 and MDCK cells. Expression and sub-cellular localization of IFT43 in the retina and transiently transfected cells was examined by RT-PCR, western blot analysis, and immunohistochemistry. Affected members were diagnosed with early onset non-syndromic progressive retinal degeneration and the presence of bone spicules distributed throughout the retina at younger ages while the older affected members showed severe central choroidal atrophy. Whole-exome sequencing analysis identified a novel homozygous c.100 G > A change in IFT43 segregating with retinal degeneration and not present in ethnicity-matched controls. Immunostaining showed IFT43 localized in the photoreceptors, and to the tip of the cilia in transfected mIMCD3 and MDCK cells. The cilia in mIMCD3 and MDCK cells expressing mutant IFT43 were found to be significantly shorter (P < 0.001) than cells expressing wild-type IFT43. Our studies identified a novel homozygous mutation in the ciliary protein IFT43 as the underlying cause of recessive inherited retinal degeneration. This is the first report demonstrating the involvement of IFT43 in retinal degeneration.

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