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James Liu, Cara Lwin, Yi He, Gavin Arno, Anthony T Moore, Andrew Webster, Laryssa A Huryn, Bin Guan, Robert B Hufnagel; Investigating the genotype-phenotype relationships of patient specific PNPLA6 mutations. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1519.
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© ARVO (1962-2015); The Authors (2016-present)
Pathogenic variants in the PNPLA6 gene cause a broad spectrum of neurological disorders such as spastic paraplegia type 39 (SPG39), Gordon-Holmes syndrome (GHS), Boucher-Neuhauser syndrome (BNHS), Laurence-Moon syndrome (LMS), and Oliver-McFarlane syndrome (OMS). PNPLA6 encodes Neuropathy Target Esterase (NTE), yet it’s unclear why NTE enzymatic dysfunction causes early childhood onset retinopathy in a subset of patients. Here, we investigate the relationship between PNPLA6 genotype-associated enzymatic activity and risk of retinal degeneration.
PNPLA6 variants were detected by NGS, sanger sequencing, and digital droplet PCR. Clinical meta-analysis was performed on 133 previously reported patients by literature search (PubMed, 2008-2020). Statistical analysis was performed in Prism. DNA constructs containing full length NTE underwent site directed mutagenesis to produce the patient specific proteins. NTE activity was determined as previously published (PMID:12791540). Intronic variants were assessed for splice alterations by minigene assay.
Biallelic pathogenic PNPLA6 variants were detected in ten patients with clinical diagnosis of SPG39, BNHS or OMS, including 7 novel variants. Clinical meta-analysis of these and 75 previously reported genotyped patients indicated significant differences in ophthalmic and endocrinologic symptom onset between clinical diagnosis categories. Intriguingly, patients with early onset retinopathy were not more likely to harbor truncating variants, and no differences in disease onset or tissues affected were found between those with and without truncating variants. To examine effects of missense alleles on phenotype, we measured activity in 17 variants observed in two or more patients with the same clinical diagnosis. Residual esterase activity of recurrent missense variants observed in patients with retinopathy was significantly lower compared to those without reported visual symptoms.
Molecular determinants of retinal disease onset is different among clinical diagnoses of PNPLA6-opathies. Enzyme activity of recurrent disease-associate missense variants indicates a relationship between enzymatic activity and likelihood of retinopathy, implicating missense variants as drivers of tissue-specific disease onset. This supports a genotype:activity:phenotype relationship among PNPLA6-opathies that may be valuable for both diagnosis and prognosis.
This is a 2021 ARVO Annual Meeting abstract.
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