IFT88 mutations identified in individuals with non-syndromic recessive retinal degeneration result in abnormal ciliogenesis

Anil Chekuri, Aditya A. Guru, Pooja Biswas, Kari Branham, Shyamanga Borooah, Angel Soto-Hermida, Michael Hicks, Naheed W. Khan, Hiroko Matsui, Akhila Alapati, Pongali B. Raghavendra, Susanne Roosing, Sripriya Sarangapani, Sinnakaruppan Mathavan, Amalio Telenti, John R. Heckenlively, Sheikh Amer Riazuddin, Kelly A. Frazer, Paul A. Sieving, Radha Ayyagari

Research output: Contribution to journalArticle

Abstract

Whole genome sequencing (WGS) was performed to identify the variants responsible for inherited retinal degeneration (IRD) in a Caucasian family. Segregation analysis of selected rare variants with pathogenic potential identified a set of compound heterozygous changes p.Arg266*:c.796C>T and p.Ala568Thr:c.1702G>A in the intraflagellar transport protein-88 (IFT88) gene segregating with IRD. Expression of IFT88 with the p.Arg266* and p.Ala568Thr mutations in mIMDC3 cells by transient transfection and in HeLa cells by introducing the mutations using CRISPR-cas9 system suggested that both mutations result in the formation of abnormal ciliary structures. The introduction of the IFT88 p.Arg266* variant in the homozygous state in HeLa cells by CRISPR-Cas9 genome-editing revealed that the mutant transcript undergoes nonsense-mediated decay leading to a significant depletion of IFT88 transcript. Additionally, abnormal ciliogenesis was observed in these cells. These observations suggest that the rare and unique combination of IFT88 alleles observed in this study provide insight into the physiological role of IFT88 in humans and the likely mechanism underlying retinal pathology in the pedigree with IRD.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalHuman Genetics
DOIs
StateAccepted/In press - Jul 5 2018

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Retinal Degeneration
Carrier Proteins
Mutation
Clustered Regularly Interspaced Short Palindromic Repeats
HeLa Cells
Pedigree
Transfection
Alleles
Genome
Pathology
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Chekuri, A., Guru, A. A., Biswas, P., Branham, K., Borooah, S., Soto-Hermida, A., ... Ayyagari, R. (Accepted/In press). IFT88 mutations identified in individuals with non-syndromic recessive retinal degeneration result in abnormal ciliogenesis. Human Genetics, 1-12. https://doi.org/10.1007/s00439-018-1897-9

IFT88 mutations identified in individuals with non-syndromic recessive retinal degeneration result in abnormal ciliogenesis. / Chekuri, Anil; Guru, Aditya A.; Biswas, Pooja; Branham, Kari; Borooah, Shyamanga; Soto-Hermida, Angel; Hicks, Michael; Khan, Naheed W.; Matsui, Hiroko; Alapati, Akhila; Raghavendra, Pongali B.; Roosing, Susanne; Sarangapani, Sripriya; Mathavan, Sinnakaruppan; Telenti, Amalio; Heckenlively, John R.; Riazuddin, Sheikh Amer; Frazer, Kelly A.; Sieving, Paul A.; Ayyagari, Radha.

In: Human Genetics, 05.07.2018, p. 1-12.

Research output: Contribution to journalArticle

Chekuri, A, Guru, AA, Biswas, P, Branham, K, Borooah, S, Soto-Hermida, A, Hicks, M, Khan, NW, Matsui, H, Alapati, A, Raghavendra, PB, Roosing, S, Sarangapani, S, Mathavan, S, Telenti, A, Heckenlively, JR, Riazuddin, SA, Frazer, KA, Sieving, PA & Ayyagari, R 2018, 'IFT88 mutations identified in individuals with non-syndromic recessive retinal degeneration result in abnormal ciliogenesis', Human Genetics, pp. 1-12. https://doi.org/10.1007/s00439-018-1897-9
Chekuri, Anil ; Guru, Aditya A. ; Biswas, Pooja ; Branham, Kari ; Borooah, Shyamanga ; Soto-Hermida, Angel ; Hicks, Michael ; Khan, Naheed W. ; Matsui, Hiroko ; Alapati, Akhila ; Raghavendra, Pongali B. ; Roosing, Susanne ; Sarangapani, Sripriya ; Mathavan, Sinnakaruppan ; Telenti, Amalio ; Heckenlively, John R. ; Riazuddin, Sheikh Amer ; Frazer, Kelly A. ; Sieving, Paul A. ; Ayyagari, Radha. / IFT88 mutations identified in individuals with non-syndromic recessive retinal degeneration result in abnormal ciliogenesis. In: Human Genetics. 2018 ; pp. 1-12.
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AU - Borooah, Shyamanga

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AU - Sarangapani, Sripriya

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AU - Telenti, Amalio

AU - Heckenlively, John R.

AU - Riazuddin, Sheikh Amer

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AU - Sieving, Paul A.

AU - Ayyagari, Radha

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