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The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy


Neutral lipid storage disease comprises a heterogeneous group of autosomal recessive disorders characterized by systemic accumulation of triglycerides in cytoplasmic droplets. Here we report a neutral lipid storage disease subgroup characterized by mild myopathy, absence of ichthyosis and mutations in both alleles of adipose triglyceride lipase (PNPLA2, also known as ATGL). Three of these mutations are predicted to lead to a truncated ATGL protein with an intact patatin domain containing the active site, but with defects in the hydrophobic domain. The block in triglyceride degradation was mimicked by short interfering RNA directed against ATGL. NLSDM is distinct from Chanarin-Dorfman syndrome, which is characterized by neutral lipid storage disease with ichthyosis, mild myopathy and hepatomegaly due to mutations in ABHD5 (also known as CGI-58).

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Figure 1: Neutral lipid accumulation and mutations in the PNPLA2 gene in individuals affected with neutral lipid storage disease with myopathy (NLSDM).
Figure 2: Predicted structure and function of normal and mutant ATGL in individuals affected with NLSDM.

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We wish to thank the patients and family members for their participation in this study. We are grateful to S. Cure for help in writing this manuscript and to J.C. Thiers for microscopy assistance. This study was supported by the Centre National de Génotypage (CNG), the Association Française contre les Myopathies (AFM), INSERM and University Paul Sabatier Toulouse-3.

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Authors and Affiliations



E.M., J.-M.M. and P.L. provided patient material and clinical information. J.F. and C.L. designed and performed the genetic part of the study, R.S. and A.N.-S. designed and performed the biochemical part of the study, M.L. provided infrastructure and J.F. and R.S. contributed to the writing of this paper.

Corresponding authors

Correspondence to Judith Fischer or Robert Salvayre.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Translated sequence of Homo sapiens ATGL. (PDF 15 kb)

Supplementary Fig. 2

ATGL mutations in patient 1. (PDF 35 kb)

Supplementary Fig. 3

ATGL mutations, continued. (PDF 33 kb)

Supplementary Table 1

Comparison of phenotypes, metablic defects and mutations. (PDF 12 kb)

Supplementary Table 2

Primer sequences. (PDF 8 kb)

Supplementary Methods (PDF 30 kb)

Supplementary Note (PDF 56 kb)

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Fischer, J., Lefèvre, C., Morava, E. et al. The gene encoding adipose triglyceride lipase (PNPLA2) is mutated in neutral lipid storage disease with myopathy. Nat Genet 39, 28–30 (2007).

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