title: Loss of function variants in human PNPLA8 encoding calcium-independent phospholipase A2 γ recapitulate the mitochondriopathy of the homologous null mouse.
abstract: Mitochondriopathies are a group of clinically heterogeneous genetic diseases caused by defects in mitochondrial metabolism, bioenergetic efficiency, and/or signaling functions. The large majority of proteins involved in mitochondrial function are encoded by nuclear genes, with many yet to be associated with human disease. We performed exome sequencing on a young girl with a suspected mitochondrial myopathy that manifested as progressive muscle weakness, hypotonia, seizures, poor weight gain, and lactic acidosis. She was compound heterozygous for two frameshift mutations, p.Asn112HisfsX29 and p.Leu659AlafsX4, in the PNPLA8 gene, which encodes mitochondrial calcium-independent phospholipase A2 γ (iPLA2 γ). Western blot analysis of affected muscle displayed the absence of PNPLA8 protein. iPLA2 s are critical mediators of a variety of cellular processes including growth, metabolism, and lipid second messenger generation, exerting their functions through catalyzing the cleavage of the acyl groups in glycerophospholipids. The clinical presentation, muscle histology and the mitochondrial ultrastructural abnormalities of this proband are highly reminiscent of Pnpla8 null mice. Although other iPLA2 -related diseases have been identified, namely, infantile neuroaxonal dystrophy and neutral lipid storage disease with myopathy, this is the first report of PNPLA8-related disease in a human. We suggest PNPLA8 join the increasing list of human genes involved in lipid metabolism associated with neuromuscular diseases due to mitochondrial dysfunction.
authors.affiliation: Center for Pediatric Genomic Medicine, Children's Mercy Hospitals, Kansas City, Missouri.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Saunders
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Moon
authors.forename: Xinping
authors.initials: X
authors.lastname: Liu
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thiffault
authors.forename: Keith
authors.initials: K
authors.lastname: Coffman
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: LePichon
authors.forename: Eugenio
authors.initials: E
authors.lastname: Taboada
authors.forename: Laurie D
authors.initials: LD
authors.lastname: Smith
authors.forename: Emily G
authors.initials: EG
authors.lastname: Farrow
authors.forename: Neil
authors.initials: N
authors.lastname: Miller
authors.forename: Margaret
authors.initials: M
authors.lastname: Gibson
authors.forename: Melanie
authors.initials: M
authors.lastname: Patterson
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Kingsmore
authors.forename: Richard W
authors.initials: RW
authors.lastname: Gross
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002648:Child; D005260:Female; D054513:Group IV Phospholipases A2 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000473:pathology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D054513:Group IV Phospholipases A2; D002118:Calcium
keywords: PNPLA8; dystonia; mitochondrial dysfunction; phospholipase