Biallelic null variants in PNPLA8 cause microcephaly!
Membrane phospholipid maintenance is carried out by a calcium-independent phospholipase A2 enzyme, platatin-like phospholipase domain-containing lipase 8 (PNPLA8).
The researchers newly identified 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide phenotypic spectrum of clinical features including degenerative epileptic–dyskinetic encephalopathy and childhood-onset neurodegeneration.
Using brain organoids generated from human induced pluripotent stem cells, they show that PNPLA8 regulates phospholipid metabolism, and that its loss leads to developmental defects by reducing the number of basal radial glia.
They show that neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. Also, reduced number of basal radial glial cells in patient-derived cerebral organoids was rescued, in part, by the addition of lysophosphatidic acid.
https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awae185/7724673
