Hypolipidaemia among patients with PMM2-CDG is associated with low circulating PCSK9 levels: a case report followed by observational and experimental studies

Journal of Medical Genetics
Michael ChongNabil G Seidah

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel therapeutics for reducing low-density lipoprotein cholesterol (LDLc). While serious side-effects have not been observed in short-term clinical trials, there remain concerns that long-term PCSK9 inhibition may cause neurocognitive side-effects. An adult male with childhood-onset global developmental delay, cerebellar atrophy and severe hypolipidaemia underwent extensive biochemical and genetic investigations. Initial testing revealed low circulating PCSK9 levels and a common loss-of-function PCSK9 polymorphism, but these findings did not fully account for severe hypolipidaemia. Whole-exome sequencing was subsequently performed and identified two pathogenic phosphomannose mutase 2 (PMM2) variants (p.Arg141His and p.Pro69Ser) known to cause PMM2-associated congenital disorder of glycosylation (PMM2-CDG). A diagnosis of PMM2-CDG was consistent with the proband's neurological symptoms and severe hypolipidaemia. Given that PMM2-CDG is characterised by defective protein N-glycosylation and that PCSK9 is a negative regulator of LDLc, we postulated that loss of PCSK9 N-glycosylation mediates hypolipidaemia among patients with PMM2-CDG. First, in an independent co...Continue Reading

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Citations

Sep 5, 2020·Cardiovascular Research·Angela PirilloGiuseppe Danilo Norata
Nov 19, 2020·Journal of Lipid Research·Carlota OleagaSergio Fazio
Feb 14, 2021·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Guillaume DorvalLaurence Heidet
Jan 12, 2021·Journal of Lipid Research·Carlota OleagaSergio Fazio
Sep 30, 2020·Biochimica Et Biophysica Acta. General Subjects·Nina OndruskovaJaak Jaeken

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