Novel duplication mutation in the patatin domain of adipose triglyceride lipase (PNPLA2) in neutral lipid storage disease with severe myopathy

Abstract

Recently, mutations in PNPLA2 encoding adipose triglyceride lipase (ATGL) were reported to underlie a neutral lipid storage disease (NLSD) subgroup characterized by mild myopathy and the absence of ichthyosis. In the present study a novel homozygous PNPLA2 mutation c.475_478dupCTCC (p.Gln160ProfsX19) in the patatin domain, the ATGL active site, was detected in a woman with NLSD and severe myopathy. The present results suggest that a premature truncation mutation in the patatin domain causes NLSD with severe myopathy.

Novel PNPLA2 gene mutations in Chinese Han patients causing neutral lipid storage disease with myopathy

“…Only one patient carrying the PNPLA2 gene mutation c.475_478dupCTCC affected the patatin domain caused severely myopathy was reported. 6 One of our patients carries the homozygous frameshift deletion mutation c.467delC, which may affect the patatin domain. Compared with other patients, the patient with the c.467delC mutation displayed similar phenotypes.…”

“…Recently, NLSDM has been attributed to mutations in the PNPLA2 gene. 3,6 PNPLA2 is the rate-limiting lipolytic enzyme and catalyzes the initial step in triglyceride hydrolysis. 1,7,8 Most individuals with PNPLA2 mutations show atypical CDS-like symptoms, with myopathy and involvement of other organs but without ichthyosis.…”

“…The patatin domain (amino acids 10-179) contains an active site with a serine-aspartate catalytic dyad and an oxyanion hole that stabilizes the enzyme-substrate transition state. 6,10 The C-terminal region contains a potential lipid binding domain at residues 309-391. 11 Most PNPLA2 mutations reported now affect the C-terminal hydrophobic domain, which is responsible for lipid binding.…”

“…Compared with other patients, the patient with the c.467delC mutation displayed similar phenotypes. 1, 3,6,[10][11][12] The result suggests that there is probably no correlation between the nature of the mutation in PNPLA2 and disease severity in NLSD. We also described two novel splicing mutations IVS6 þ 1G4T and IVS6 þ 2T4C of PNPLA2.…”

Genetics, physiology and perinatal influences in childhood obesity: view from the Chair

“…Primary genetic defects have been described in humans, in whom ATGL mutations cause an adult-onset skeletal myopathy. 46,47 The phenotypic difference with mice has not been explained. Some human mutations may retain partial activity, explaining the less serious phenotype.…”