Mutations in SPATA13/ASEF2 cause primary angle closure glaucoma

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

Molecular Genetics of Glaucoma: Subtype and Ethnicity Considerations

“…As opposed to Asian populations, the prevalence of PACG is low in Europe (0.42%) and North America (0.26%) [ 25 , 126 ], and genetic data on PACG in ED is generally lacking [ 126 ]. The low prevalence makes study and identification of affected ED families difficult [ 156 ].…”

“…More recently, in 2020, Waseem, et al conducted a study of PACG in an ED family in the UK [ 156 ]. They studied 39 blood-related patients, 5 of which were unaffected (penetrance 87.2%).…”

“…When SPATA13 was then studied in a cohort of 189 unrelated individuals, the researchers found eight additional mutations associated with PACG. Importantly, this was the first study to identify SPATA13 as a gene that was associated with both PACG and any eye disease, though GWAS have implicated the gene product (protein SP-1277) with other disorders such as anorexia nervosa, thyroid cancer, and intellectual disability [ 156 ].…”

“…Ultimately, given the difficulties of replicating GWAS and PRS across ethnicities [ 34 , 36 ], further studies are needed to address PACG in LAD and AD populations. Next steps may include performing WES in PACG-impacted families (similar to Waseem, et al in the UK [ 156 ]), or gathering large databases of glaucoma patients across the regions to prepare for GWAS, or even single-gene analysis, in such populations where PACG prevalence is low.…”

Updates on Genes and Genetic Mechanisms Implicated in Primary Angle-Closure Glaucoma

“…In another recent study using a combination of linkage and whole-genome sequencing, Waseem et al identified a causal genetic variant in SPATA13 (spermatogenesis associated protein 13) in a seven-generation PACG family of British origin. 196 A single 9bp in-frame deletion variant (c.1432_1440del; p.478_480del) in SPATA13 on chromosome 13q12.12 was found to segregate in all the affected individuals of the family with variable expression and decreased penetrance. Additional rare variants in SPATA13 were also observed in unrelated PACS, PAC or PACG cohorts, including the 9bp deletion, supporting the causal evidence of this variant.…”