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 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.

PCDH19‐related epileptic encephalopathy in a male mosaic for a truncating variant

“…DNA was prepared utilizing the KAPA Biosystems library preparation kit (KAPA Biosystems, Woburn, MA) followed by Illumina TruSeqExome enrichment (Illumina, San Diego, CA). Alignment and variant calling was performed as previously published [Soden et al, ; Saunders et al, ,]. Using custom‐developed software, RUNES, and VIKING, variants were filtered to 1% minor allele frequency, then prioritized by the American College of Medical Genetics (ACMG) categorization, OMIM (http://www.omim.org) identity and phenotypic assessment.…”

A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies

“…iPLA2γ (PNPLA8) is known to be involved in cardiolipin biosynthesis and mitochondrial respiration[ 27 , 28 ]. Recently, mutations in human PNPLA8 identified in a young girl with a suspected mitochondrial myopathy[ 29 ]. She presented with progressive muscle weakness, hypotonia, seizures, poor weight gain, and lactic acidosis.…”

Allele, phenotype and disease data at Mouse Genome Informatics: improving access and analysis

“…Data provided by studies of the laboratory mouse have been shown to be valuable in driving discovery of human disease mutations. For example, a recent study describes the discovery of a variant of human PNPLA8 that causes mitochondrial myopathy (OMIM 251950, Saunders et al 2015 ). A mouse mutation in this gene with a similar phenotype had been previously described in Mancuso et al 2009 .…”