title: Biallelic mutations in PLA2G5, encoding group V phospholipase A2, cause benign fleck retina.
abstract: Flecked-retina syndromes, including fundus flavimaculatus, fundus albipunctatus, and benign fleck retina, comprise a group of disorders with widespread or limited distribution of yellow-white retinal lesions of various sizes and configurations. Three siblings who have benign fleck retina and were born to consanguineous parents are the basis of this report. A combination of homozygosity mapping and exome sequencing helped to identify a homozygous missense mutation, c.133G>T (p.Gly45Cys), in PLA2G5, a gene encoding a secreted phospholipase (group V phospholipase A(2)). A screen of a further four unrelated individuals with benign fleck retina detected biallelic variants in the same gene in three patients. In contrast, no loss of function or common (minor-allele frequency>0.05%) nonsynonymous PLA2G5 variants have been previously reported (EVS, dbSNP, 1000 Genomes Project) or were detected in an internal database of 224 exomes (from subjects with adult onset neurodegenerative disease and without a diagnosis of ophthalmic disease). All seven affected individuals had fundoscopic features compatible with those previously described in benign fleck retina and no visual or electrophysiological deficits. No medical history of major illness was reported. Levels of low-density lipoprotein were mildly elevated in two patients. Optical coherence tomography and fundus autofluorescence findings suggest that group V phospholipase A(2) plays a role in the phagocytosis of photoreceptor outer-segment discs by the retinal pigment epithelium. Surprisingly, immunohistochemical staining of human retinal tissue revealed localization of the protein predominantly in the inner and outer plexiform layers.
authors.affiliation: Institute of Ophthalmology, University College London, London, UK.
authors.forename: Panagiotis I
authors.initials: PI
authors.lastname: Sergouniotis
authors.forename: Alice E
authors.initials: AE
authors.lastname: Davidson
authors.forename: Donna S
authors.initials: DS
authors.lastname: Mackay
authors.forename: Eva
authors.initials: E
authors.lastname: Lenassi
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Robson
authors.forename: Xu
authors.initials: X
authors.lastname: Yang
authors.forename: Jaimie Hoh
authors.initials: JH
authors.lastname: Kam
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Isaacs
authors.forename: Graham E
authors.initials: GE
authors.lastname: Holder
authors.forename: Glen
authors.initials: G
authors.lastname: Jeffery
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Beck
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Moore
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D003241:Consanguinity; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D054505:Group V Phospholipases A2 / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D021381:Protein Transport; D012160:Retina / Q000002:abnormalities* / Q000378:metabolism
chemical_list: D054505:Group V Phospholipases A2; C516299:PLA2G5 protein, human