Mutations in SPATA13/ASEF2 cause primary angle closure glaucoma

Autoři: Naushin H. Waseem aff001;  Sancy Low aff002;  Amna Z. Shah aff003;  Deepa Avisetti aff005;  Pia Ostergaard aff006;  Michael Simpson aff007;  Katarzyna A. Niemiec aff005;  Belen Martin-Martin aff008;  Hebah Aldehlawi aff005;  Saima Usman aff005;  Pak Sang Lee aff001;  Anthony P. Khawaja aff001;  Jonathan B. Ruddle aff009;  Ameet Shah aff010;  Ege Sackey aff006;  Alexander Day aff002;  Yuzhen Jiang aff002;  Geoff Swinfield aff011;  Ananth Viswanathan aff001;  Giovanna Alfano aff003;  Christina Chakarova aff003;  Heather J. Cordell aff012;  David F. Garway-Heath aff001;  Peng T. Khaw aff001;  Shomi S. Bhattacharya aff001;  Ahmad Waseem aff005;  Paul J. Foster aff001
Působiště autorů: NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, United Kingdom aff001;  Moorfields Eye Hospital NHS Foundation Trust, City Road, London, United Kingdom aff002;  UCL Institute of Ophthalmology, Bath Street, London, United Kingdom aff003;  Department of Ophthalmology, St. Thomas’ Hospital, Westminster Bridge Road, London, United Kingdom aff004;  Centre for Oral Immunobiology and Regenerative Medicine, Institute of Dentistry, Queen Mary University of London, London, United Kingdom aff005;  Medical Genetics Unit, St. George’s University of London, Cranmer Terrace, London, United Kingdom aff006;  Genetics and Molecular Medicine, King’s College London, Great Maze Pond, London, United Kingdom aff007;  Blizard Advanced Light Microscopy, Blizard Institute, Queen Mary University of London, London, United Kingdom aff008;  Department of Ophthalmology, University of Melbourne, Victoria, Australia aff009;  Department of Ophthalmology, Royal Free Hospital NHS Foundation Trust, Pond Street, London, United Kingdom aff010;  Society of Genealogists, Goswell Road, London, United Kingdom aff011;  Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom aff012
Vyšlo v časopise: Mutations in SPATA13/ASEF2 cause primary angle closure glaucoma. PLoS Genet 16(4): e32767. doi:10.1371/journal.pgen.1008721
Kategorie: Research Article


Current estimates suggest 50% of glaucoma blindness worldwide is caused by primary angle-closure glaucoma (PACG) but the causative gene is not known. We used genetic linkage and whole genome sequencing to identify Spermatogenesis Associated Protein 13, SPATA13 (NM_001166271; NP_001159743, SPATA13 isoform I), also known as ASEF2 (Adenomatous polyposis coli-stimulated guanine nucleotide exchange factor 2), as the causal gene for PACG in a large seven-generation white British family showing variable expression and incomplete penetrance. The 9 bp deletion, c.1432_1440del; p.478_480del was present in all affected individuals with angle-closure disease. We show ubiquitous expression of this transcript in cell lines derived from human tissues and in iris, retina, retinal pigment and ciliary epithelia, cornea and lens. We also identified eight additional mutations in SPATA13 in a cohort of 189 unrelated PACS/PAC/PACG samples. This gene encodes a 1277 residue protein which localises to the nucleus with partial co-localisation with nuclear speckles. In cells undergoing mitosis SPATA13 isoform I becomes part of the kinetochore complex co-localising with two kinetochore markers, polo like kinase 1 (PLK-1) and centrosome-associated protein E (CENP-E). The 9 bp deletion reported in this study increases the RAC1-dependent guanine nucleotide exchange factors (GEF) activity. The increase in GEF activity was also observed in three other variants identified in this study. Taken together, our data suggest that SPATA13 is involved in the regulation of mitosis and the mutations dysregulate GEF activity affecting homeostasis in tissues where it is highly expressed, influencing PACG pathogenesis.

Klíčová slova:

Cornea – Epithelium – Eyes – Glaucoma – Immunohistochemistry techniques – Mutation – Nuclear staining – Guanine nucleotide exchange factors


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