Recessive Mutations in the PLA2G5 Gene, Encoding Group V Phospholipase A2, Cause Benign Fleck Retina

Abstract

Purpose: : To determine the molecular pathology of benign fleck retina, an autosomal recessive condition associated with yellow-white, fleck-like retinal lesions and no apparent visual or electrophysiological deficits.

Methods: : Single-nucleotide polymorphism arrays (Affymetrix) were utilised to perform homozygosity mapping in a consanguineous family with three affected siblings (family J). Subsequently, DNA from an affected family member was analysed using exon capture and high-throughput sequencing (Agilent SureSelect 38 Mb exome, Illumina HiSeq2000 sequencer). Sanger sequencing of PLA2G5 was performed on DNA from four additional unrelated individuals with benign fleck retina. Clinical investigations performed included spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence imaging, electrophysiology and fundus-controlled perimetry. Immunohistochemistry on human retinal sections was undertaken to determine the precise localisation of group V phospholipase A2 (PLA2).

Results: : A homozygous, likely disease-associated missense variant in PLA2G5 (c.133G>T, p.Gly45Cys) was identified in affected individuals from family J. Biallelic missense and nonsense changes in the same gene were detected in three additional patients with the same diagnosis. In contrast, no loss of function or common (minor-allele frequency > 0.05%) non-synonymous PLA2G5 variants have been previously reported (exome variant server, dbSNP, 1000 genomes project) or were detected in an internal database of 224 exomes. No visual or electrophysiological deficits were detected in any patient. SD-OCT and fundus autofluorescence imaging revealed endogenously fluorescent lesions at the level of the retinal pigment epithelium. Despite defective group V PLA2 being associated with conditions such as asthma and atherosclerosis in Pla2g5-deficient mice, patients did not report any medical history of major illness; two had mildly elevated low-density lipoprotein levels. Unexpectedly, immunohistochemical staining of human retinal tissue revealed localization of the protein predominantly in the inner and outer plexiform layers.

Conclusions: : Defects in a secretory phospholipase, group V phospholipase A2, cause benign fleck retina. This finding facilitates differential diagnosis of this benign condition from other fleck retina syndromes associated with abnormal retinal function. The composition of the flecks and the precise role of group V PLA2 in the human retina remain to be determined.

Keywords: genetics • retina • gene mapping