Loss of Function Variants in Human PNPLA8 Encoding Calcium-Independent Phospholipase A2γ 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 A2γ (iPLA2γ). Western blot analysis of affected muscle displayed the absence of PNPLA8 protein. iPLA2s 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.