Mutations in SPATA13/ASEF2 cause primary angle closure glaucoma.

Naushin Waseem ,Christina Chakarova,Ahmad Waseem,Hebah Aldehlawi,Giovanna Alfano,Yuzhen Jiang,Pak Sang Lee,Heather J Cordell,Anthony P Khawaja,Ege Sackey,Katarzyna A Niemiec,Paul J Foster,Ameet Shah,Sancy Low,Geoff Swinfield,Saima Usman,Siladitya Bhattacharya ,Michael A Simpson ,Peng Tee Khaw ,Pia Østergaard ,Alexander C Day ,Ananth C Viswanathan ,Jonathan B Ruddle ,Belén Martı́n-Martı́n ,Deepa R Avisetti ,David Garway-Heath

doi:10.1371/journal.pgen.1008721

Abstract

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.

Highlights

Glaucoma is the most common cause of irreversible blindness worldwide, affecting nearly 80 million people [1]
We report the identification and functional characterisation of the first gene, mutation in which causes primary angle closure glaucoma in a seven generation Caucasian family
Identification of the disease-causing role of mutations in this gene helps to further the understanding of glaucoma aetiology and identifies potential therapeutic targets for disease management

Summary

Introduction

Glaucoma is the most common cause of irreversible blindness worldwide, affecting nearly 80 million people [1]. It is characterised by an intermittently progressive optic neuropathy, often culminating in loss of vision if left untreated [2]. Two main subtypes are primary open angle glaucoma (POAG) [3] and primary angle closure glaucoma (PACG)[2]. PACG accounts for a quarter of all glaucoma, but causes half of all glaucoma blindness [4]. Physical obstruction of the aqueous humor outflow channels and consequent elevation of pressure inside the eye, are hallmarks of this disease. PACG occurs in eyes that are smaller than average. PACG occurs in eyes that are smaller than average. [5]

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