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, S. 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
    Pages (from-to)447-458
    Number of pages12
    JournalHuman Genetics
    Volume137
    Issue number6-7
    DOIs
    Publication statusPublished - 01-07-2018

    Fingerprint

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

    All Science Journal Classification (ASJC) codes

    • Genetics
    • Genetics(clinical)

    Cite this

    Chekuri, A., Guru, A. A., Biswas, P., Branham, K., Borooah, S., Soto-Hermida, A., ... Ayyagari, R. (2018). IFT88 mutations identified in individuals with non-syndromic recessive retinal degeneration result in abnormal ciliogenesis. Human Genetics, 137(6-7), 447-458. 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, S. 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 ; Vol. 137, No. 6-7. pp. 447-458.
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    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.",
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    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, vol. 137, no. 6-7, pp. 447-458. 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, S. Amer; Frazer, Kelly A.; Sieving, Paul A.; Ayyagari, Radha.

    In: Human Genetics, Vol. 137, No. 6-7, 01.07.2018, p. 447-458.

    Research output: Contribution to journalArticle

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    T1 - IFT88 mutations identified in individuals with non-syndromic recessive retinal degeneration result in abnormal ciliogenesis

    AU - Chekuri, Anil

    AU - Guru, Aditya A.

    AU - Biswas, Pooja

    AU - Branham, Kari

    AU - Borooah, Shyamanga

    AU - Soto-Hermida, Angel

    AU - Hicks, Michael

    AU - Khan, Naheed W.

    AU - Matsui, Hiroko

    AU - Alapati, Akhila

    AU - Raghavendra, Pongali B.

    AU - Roosing, Susanne

    AU - Sarangapani, Sripriya

    AU - Mathavan, Sinnakaruppan

    AU - Telenti, Amalio

    AU - Heckenlively, John R.

    AU - Riazuddin, S. Amer

    AU - Frazer, Kelly A.

    AU - Sieving, Paul A.

    AU - Ayyagari, Radha

    PY - 2018/7/1

    Y1 - 2018/7/1

    N2 - 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.

    AB - 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.

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