TY - JOUR
T1 - Loss of function variants in human PNPLA8 encoding calcium-independent phospholipase A2γ recapitulate the mitochondriopathy of the homologous null mouse
AU - Saunders, Carol J.
AU - Moon, Sung Ho
AU - Liu, Xinping
AU - Thiffault, Isabelle
AU - Coffman, Keith
AU - Lepichon, Jean Baptiste
AU - Taboada, Eugenio
AU - Smith, Laurie D.
AU - Farrow, Emily G.
AU - Miller, Neil
AU - Gibson, Margaret
AU - Patterson, Melanie
AU - Kingsmore, Stephen F.
AU - Gross, Richard W.
N1 - Publisher Copyright:
© 2014 WILEY PERIODICALS, INC.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - 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.
AB - 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.
KW - Dystonia
KW - Mitochondrial dysfunction
KW - PNPLA8
KW - Phospholipase
UR - http://www.scopus.com/inward/record.url?scp=84924576154&partnerID=8YFLogxK
U2 - 10.1002/humu.22743
DO - 10.1002/humu.22743
M3 - Article
C2 - 25512002
AN - SCOPUS:84924576154
SN - 1059-7794
VL - 36
SP - 301
EP - 306
JO - Human mutation
JF - Human mutation
IS - 3
ER -