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

Hum Genet. 2021 Apr;140(4):649-666. doi: 10.1007/s00439-020-02238-z.

Muhammad Ali ¹, Shahid Y Khan ^# ¹, Tony A Rodrigues ^# ² ³ ⁴, Tânia Francisco ² ³ ⁴, Xiaodong Jiao ⁵, Hang Qi ⁵, Firoz Kabir ¹ ⁶, Bushra Irum ¹ ⁶, Bushra Rauf ¹ ⁶, Asma A Khan ⁶, Azra Mehmood ⁶, Muhammad Asif Naeem ⁶, Muhammad Zaman Assir ⁷, Muhammad Hassaan Ali ⁷, Mohsin Shahzad ⁸ ⁹, Khaled K Abu-Amero ¹⁰, Shehla Javed Akram ¹¹, Javed Akram ¹², Sheikh Riazuddin ⁷ ⁸ ⁹, Saima Riazuddin ¹³, Michael L Robinson ¹⁴, Myriam Baes ¹⁵, Jorge E Azevedo ^# ² ³ ⁴, J Fielding Hejtmancik ^# ⁵, S Amer Riazuddin ^# ¹⁶

Affiliations

1 The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore MD, USA.
2 Instituto de Biologia Celular E Molecular, Universidade Do Porto, Porto, Portugal.
3 Instituto de Investigação E Inovação Em Saúde, Universidade Do Porto, Porto, Portugal.
4 Instituto de Ciências Biomédicas Abel Salazar, Universidade Do Porto, Porto, Portugal.
5 Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
6 National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
7 Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan.
8 Jinnah Burn and Reconstructive Surgery Center, Jinnah Hospital, Lahore, Pakistan.
9 Department of Molecular Biology, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
10 Department of Ophthalmology and Visual Sciences, College of Medicine, University of Illinois, Chicago, IL, USA.
11 Akram Medical Complex, Lahore, Pakistan.
12 University of Health Sciences, Lahore, Pakistan.
13 Department of Otorhinolaryngology - Head and Neck Surgery, University of Maryland School Medicine, Baltimore, MD, USA.
14 Department of Biology, Miami University, Oxford, OH, USA.
15 Department of Pharmaceutical and Pharmacological Sciences, Lab of Cell Metabolism, University of Leuven, Leuven, Belgium.
16 The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore MD, USA. riazuddin@jhmi.edu.
# Contributed equally.

PMID: 33389129 DOI: 10.1007/s00439-020-02238-z

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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