SPATA13 – Primary Angle-Closure Glaucoma

SPATA13 was identified as the causal gene for primary angle-closure glaucoma (PACG) through linkage and whole-genome sequencing in a seven-generation white British family. A 9 bp in-frame deletion in SPATA13, c.1432_1440del (p.Glu478_Glu480del), segregated with angle-closure disease in all affected family members (PMID:32339198). Affected individuals exhibited variable expression and incomplete penetrance. SPATA13 encodes a 1277-residue guanine nucleotide exchange factor (GEF) that localizes to the nucleus and associates with kinetochore markers during mitosis. Ubiquitous expression was demonstrated in iris, retina, retinal pigment epithelium, ciliary epithelium, cornea, and lens (PMID:32339198).

In an independent cohort of 189 unrelated PACS/PAC/PACG patients, eight additional distinct SPATA13 variants were identified (PMID:32339198). These include missense and small indel changes affecting the GEF domain. Combined, nine unique SPATA13 variants were found in nine probands (PMID:32339198). The inheritance pattern is autosomal dominant with variable penetrance. Phenotypes ranged from primary angle-closure suspect to fully developed PACG, supporting a spectrum of disease severity.

Segregation of the c.1432_1440del variant across seven generations confirms familial linkage and co-segregation with disease (PMID:32339198). Although exact counts of affected relatives were not provided, transmission across multiple meioses underscores a strong segregation signal. The eight additional variants were identified as singleton cases without family data. No de novo occurrences have been reported. Further pedigree analysis is warranted to fully quantify segregation metrics.

The SPATA13 variant spectrum comprises one in-frame deletion (c.1432_1440del; p.Glu478_Glu480del) and eight missense or indel changes clustering within the GEF domain. No recurrent founder alleles have been described to date. Population frequency data are limited due to the rarity of these variants. The concentration of pathogenic changes in functional domains suggests allelic heterogeneity. Hypomorphic or deep-intronic variants have not yet been reported.

Functional assays demonstrate that c.1432_1440del increases RAC1-dependent GEF activity relative to wild-type SPATA13 in cell-based assays (PMID:32339198). Three other patient-derived variants also elevated GEF activity, indicating a gain-of-function mechanism. Phosphorylation of serine 106 modulates Asef2 GEF activity and cell migration, implicating post-translational regulation in disease expressivity (PMID:24874604). Localization studies show SPATA13 integration into the kinetochore complex with PLK-1 and CENP-E during mitosis. These concordant functional data support dysregulated mitotic homeostasis as the pathogenic mechanism.

No studies to date have refuted the association of SPATA13 variants with PACG. The integration of co-segregation, replication in independent patients, and concordant functional assays yields a Moderate ClinGen classification for SPATA13–PACG. Additional large-scale population screening and extended segregation analyses could elevate this to Strong. Clinically, SPATA13 genetic testing may inform risk stratification and early intervention in families predisposed to angle-closure glaucoma. Key take-home: SPATA13 gain-of-function variants underlie autosomal dominant primary angle-closure glaucoma via dysregulated RAC1-mediated GEF activity.

References

• PLoS genetics • 2020 • Mutations in SPATA13/ASEF2 cause primary angle closure glaucoma. PMID:32339198
• Journal of proteome research • 2014 • Phosphorylation of serine 106 in Asef2 regulates cell migration and adhesion turnover. PMID:24874604

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