A mutation in IFT43 causes non-syndromic recessive retinal degeneration

Pooja Biswas, Jacque L. Duncan, Muhammad Ali, Hiroko Matsui, Muhammad Asif Naeem, Pongali B. Raghavendra, Kelly A. Frazer, Heleen H. Arts, Sheikh Riazuddin, Javed Akram, Fielding F. Hejtmancik, Amer A. Riazuddin, Radha Ayyagari

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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.100G > 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.

Original languageEnglish
Pages (from-to)4741-4751
Number of pages11
JournalHuman Molecular Genetics
Volume26
Issue number23
DOIs
Publication statusPublished - 01-12-2017

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Retinal Degeneration
Carrier Proteins
Mutation
Madin Darby Canine Kidney Cells
Exome
Retina
Cilia
Inheritance Patterns
Protein Transport
Pedigree
Genes
Atrophy
Western Blotting
Immunohistochemistry
Bone and Bones
Polymerase Chain Reaction
Brain

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Biswas, P., Duncan, J. L., Ali, M., Matsui, H., Naeem, M. A., Raghavendra, P. B., ... Ayyagari, R. (2017). A mutation in IFT43 causes non-syndromic recessive retinal degeneration. Human Molecular Genetics, 26(23), 4741-4751. https://doi.org/10.1093/hmg/ddx356
Biswas, Pooja ; Duncan, Jacque L. ; Ali, Muhammad ; Matsui, Hiroko ; Naeem, Muhammad Asif ; Raghavendra, Pongali B. ; Frazer, Kelly A. ; Arts, Heleen H. ; Riazuddin, Sheikh ; Akram, Javed ; Hejtmancik, Fielding F. ; Riazuddin, Amer A. ; Ayyagari, Radha. / A mutation in IFT43 causes non-syndromic recessive retinal degeneration. In: Human Molecular Genetics. 2017 ; Vol. 26, No. 23. pp. 4741-4751.
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Biswas, P, Duncan, JL, Ali, M, Matsui, H, Naeem, MA, Raghavendra, PB, Frazer, KA, Arts, HH, Riazuddin, S, Akram, J, Hejtmancik, FF, Riazuddin, AA & Ayyagari, R 2017, 'A mutation in IFT43 causes non-syndromic recessive retinal degeneration', Human Molecular Genetics, vol. 26, no. 23, pp. 4741-4751. https://doi.org/10.1093/hmg/ddx356

A mutation in IFT43 causes non-syndromic recessive retinal degeneration. / Biswas, Pooja; Duncan, Jacque L.; Ali, Muhammad; Matsui, Hiroko; Naeem, Muhammad Asif; Raghavendra, Pongali B.; Frazer, Kelly A.; Arts, Heleen H.; Riazuddin, Sheikh; Akram, Javed; Hejtmancik, Fielding F.; Riazuddin, Amer A.; Ayyagari, Radha.

In: Human Molecular Genetics, Vol. 26, No. 23, 01.12.2017, p. 4741-4751.

Research output: Contribution to journalArticle

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T1 - A mutation in IFT43 causes non-syndromic recessive retinal degeneration

AU - Biswas, Pooja

AU - Duncan, Jacque L.

AU - Ali, Muhammad

AU - Matsui, Hiroko

AU - Naeem, Muhammad Asif

AU - Raghavendra, Pongali B.

AU - Frazer, Kelly A.

AU - Arts, Heleen H.

AU - Riazuddin, Sheikh

AU - Akram, Javed

AU - Hejtmancik, Fielding F.

AU - Riazuddin, Amer A.

AU - Ayyagari, Radha

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Biswas P, Duncan JL, Ali M, Matsui H, Naeem MA, Raghavendra PB et al. A mutation in IFT43 causes non-syndromic recessive retinal degeneration. Human Molecular Genetics. 2017 Dec 1;26(23):4741-4751. https://doi.org/10.1093/hmg/ddx356