Mutations in the PCYT1A gene are responsible for isolated forms of retinal dystrophy

Abstract

Mutations in the PCYT1A gene have been recently linked to two different phenotypes: one characterized by spondylometaphyseal dysplasia and cone-rod dystrophy (SMD-CRD) and the other by congenital lipodystrophy, severe fatty liver disease, and reduced HDL cholesterol without any retinal or skeletal involvement. Here, we identified, by next generation sequencing, sequence variants affecting function in the PCYT1A gene in three young patients with isolated retinal dystrophy from two different Italian families. A thorough clinical evaluation of the patients, with whole skeleton X-ray, metabolic assessment and liver ultrasound failed to reveal signs of skeletal dysplasia, metabolic and hepatic alterations. This is the first report showing that the PCYT1A gene can be responsible for isolated forms of retinal dystrophy, particularly without any skeletal involvement, thus further expanding the phenotypic spectrum induced by mutations in this gene.

PCYT1A Regulates Phosphatidylcholine Homeostasis from the Inner Nuclear Membrane in Response to Membrane Stored Curvature Elastic Stress

“…Given the compelling structural and in vitro evidence that PCYT1A is activated by membrane association, we hypothesized that PCYT1A was likely to be membrane-bound at key developmental stages that require organelle membrane biogenesis. To test this, we initially focused on tissues affected in PCYT1A- linked human diseases, namely retina, bone growth plates, liver, and adipose tissue ( Testa et al., 2017 , Hoover-Fong et al., 2014 , Payne et al., 2014 , Wong, 2014 , Yamamoto et al., 2014 ), where, accordingly, PCYT1A activity is likely to be physiologically important. We validated an antibody that reliably detects endogenous PCYT1A ( Figure S1 B) and immunostained cells from each of the affected tissues in mice ( Figures 1 B–1E).…”

“…Although the enzymology of PCYT1A/B and the biochemical pathways that generate PC have been well described, exactly how cells detect the levels of PC within their membranes to maintain homeostasis in vivo remains unclear ( Cornell, 2016 ). Our interest in this question was stimulated by recent reports linking biallellic loss-of-function mutations in human PCYT1A to an intriguing spectrum of specific phenotypes including retinal dystrophy, spondylometaphyseal (growth plate) dysplasia, lipodystrophy, and non-alcoholic fatty liver disease ( Testa et al., 2017 , Hoover-Fong et al., 2014 , Payne et al., 2014 , Wong, 2014 , Yamamoto et al., 2014 ). At least some of these mutations result in almost complete loss of PCYT1A expression, and significantly impair PC synthesis in primary skin fibroblasts ( Payne et al., 2014 ).…”

Disease-linked mutations in the phosphatidylcholine regulatory enzyme CCTα impair enzymatic activity and fold stability

“…Three of these alleles (V142M, E280del, and S333Lfs.164) are linked to lipodystrophy, characterized by dyslipidemia, low high density lipoprotein cholesterol levels, absence of peripheral adipose tissue, fatty liver disease, diabetes, insulin resistance, and short stature (20). Three alleles were found in patients with isolated retinal dystrophy (A93T, R283*, and L299*17) (21). R283* and the other nine alleles are linked to spondylometaphyseal dysplasia with cone-rod dystrophy (SMD-CRD), characterized by dwarfism, skeletal malformation, and vision impairment due to degeneration of rods and cones (19,22).…”

Loss of function variants inPCYT1Acausing spondylometaphyseal dysplasia with cone/rod dystrophy have broad consequences on lipid metabolism, chondrocyte differentiation, and lipid droplet formation

“…These observations suggest that the shared allele may account for the distinctive phenotype in these patients. Testa et al (2017) reported a third class of patients with biallelic PCYT1A variants and retinal degeneration, without accompanying skeletal dysplasia or lipodystrophy [4]. The two probands shared a common PCYT1A missense variant (c.277G>A, p.Ala93Thr) in trans to a splice site or nonsense variant in the second allele (c.897+1G>A or c.847C>T, p.Arg283*, respectively).…”