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A missense allele of PEX5 is responsible for the defective import of PTS2 cargo proteins into peroxisomes

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Abstract

Peroxisomes, single-membrane intracellular organelles, play an important role in various metabolic pathways. The translocation of proteins from the cytosol to peroxisomes depends on peroxisome import receptor proteins and defects in peroxisome transport result in a wide spectrum of peroxisomal disorders. Here, we report a large consanguineous family with autosomal recessive congenital cataracts and developmental defects. Genome-wide linkage analysis localized the critical interval to chromosome 12p with a maximum two-point LOD score of 4.2 (θ = 0). Next-generation exome sequencing identified a novel homozygous missense variant (c.653 T > C; p.F218S) in peroxisomal biogenesis factor 5 (PEX5), a peroxisome import receptor protein. This missense mutation was confirmed by bidirectional Sanger sequencing. It segregated with the disease phenotype in the family and was absent in ethnically matched control chromosomes. The lens-specific knockout mice of Pex5 recapitulated the cataractous phenotype. In vitro import assays revealed a normal capacity of the mutant PEX5 to enter the peroxisomal Docking/Translocation Module (DTM) in the presence of peroxisome targeting signal 1 (PTS1) cargo protein, be monoubiquitinated and exported back into the cytosol. Importantly, the mutant PEX5 protein was unable to form a stable trimeric complex with peroxisomal biogenesis factor 7 (PEX7) and a peroxisome targeting signal 2 (PTS2) cargo protein and, therefore, failed to promote the import of PTS2 cargo proteins into peroxisomes. In conclusion, we report a novel missense mutation in PEX5 responsible for the defective import of PTS2 cargo proteins into peroxisomes resulting in congenital cataracts and developmental defects.

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Acknowledgements

The authors are grateful to all the members for their participation in this study. The work was supported by National Eye Institute Grant R01EY022714 (SAR). Work in JEA Laboratory was financed by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020—Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project PTDC/BEX-BCM/2311/2014 (POCI-01-0145-FEDER-016613) and the projects "Institute for Research and Innovation in Health Sciences" (POCI-01-0145-FEDER-007274) and NORTE-01-0145-FEDER-000008 -Porto Neurosciences and Neurologic Disease Research Initiative at I3S, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). TF and TAR are supported by Fundação para a Ciência e Tecnologia, Programa Operacional Potencial Humano do QREN, and Fundo Social Europeu.

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Author notes

  1. Muhammad Ali, Shahid Y. Khan and Tony A. Rodrigues contributed equally to the manuscript and should be considered co-first authors.

  2. Jorge E. Azevedo, J. Fielding Hejtmancik and S. Amer Riazuddin contributed equally to the manuscript and should be considered co-senior authors.

Authors and Affiliations

  1. The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore MD, USA

    Muhammad Ali, Shahid Y. Khan, Firoz Kabir, Bushra Irum, Bushra Rauf & S. Amer Riazuddin

  2. Instituto de Biologia Celular E Molecular, Universidade Do Porto, Porto, Portugal

    Tony A. Rodrigues, Tânia Francisco & Jorge E. Azevedo

  3. Instituto de Investigação E Inovação Em Saúde, Universidade Do Porto, Porto, Portugal

    Tony A. Rodrigues, Tânia Francisco & Jorge E. Azevedo

  4. Instituto de Ciências Biomédicas Abel Salazar, Universidade Do Porto, Porto, Portugal

    Tony A. Rodrigues, Tânia Francisco & Jorge E. Azevedo

  5. Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA

    Xiaodong Jiao, Hang Qi & J. Fielding Hejtmancik

  6. National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan

    Firoz Kabir, Bushra Irum, Bushra Rauf, Asma A. Khan, Azra Mehmood & Muhammad Asif Naeem

  7. Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan

    Muhammad Zaman Assir, Muhammad Hassaan Ali & Sheikh Riazuddin

  8. Jinnah Burn and Reconstructive Surgery Center, Jinnah Hospital, Lahore, Pakistan

    Mohsin Shahzad & Sheikh Riazuddin

  9. Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan

    Mohsin Shahzad & Sheikh Riazuddin

  10. Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois, Chicago, IL, USA

    Khaled K. Abu-Amero

  11. Akram Medical Complex, Lahore, Pakistan

    Shehla Javed Akram

  12. University of Health Sciences, Lahore, Pakistan

    Javed Akram

  13. Department of Otorhinolaryngology - Head and Neck Surgery, University of Maryland School Medicine, Baltimore, MD, USA

    Saima Riazuddin

  14. Department of Biology, Miami University, Oxford, OH, USA

    Michael L. Robinson

  15. Department of Pharmaceutical and Pharmacological Sciences, Lab of Cell Metabolism, University of Leuven, Leuven, Belgium

    Myriam Baes

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  1. Muhammad Ali
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Contributions

MA, SYK, SAR: conceived and designed the experiments; SR, MLR, MB, JEA, JFH, SAR: contributed reagents, materials, and analytical tools; MA, SYK, TAR, TF, FK, BI, and BR: performed experiments; AAK, AM, MAN, MZA, MHA, MS, SJK, JK, SR: enrolled human subjects and ascertained clinical evaluations; MA, SYK, TAR, TF, XJ, HQ, FK, KKA, SR, SR, MLR, MB, JEA, JFH, SAR: data analysis and critical review of the manuscript; MA, SYK, TAR, TF, SR, SR, MLR, MB, JEA, JFH, SAR: contributed to writing the manuscript.

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Correspondence to S. Amer Riazuddin.

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Ali, M., Khan, S.Y., Rodrigues, T.A. et al. A missense allele of PEX5 is responsible for the defective import of PTS2 cargo proteins into peroxisomes. Hum Genet 140, 649–666 (2021). https://doi.org/10.1007/s00439-020-02238-z

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