Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin

Abstract

Mice carrying mutations in the fatty liver dystrophy (fld) gene have features of human lipodystrophy1, a genetically heterogeneous group of disorders characterized by loss of body fat, fatty liver, hypertriglyceridemia and insulin resistance2,3,4. Through positional cloning, we have isolated the gene responsible and characterized two independent mutant alleles, fld and fld2J. The gene (Lpin1) encodes a novel nuclear protein which we have named lipin. Consistent with the observed reduction of adipose tissue mass in fld and fld2J mice, wild-type Lpin1 mRNA is expressed at high levels in adipose tissue and is induced during differentiation of 3T3-L1 pre-adipocytes. Our results indicate that lipin is required for normal adipose tissue development, and provide a candidate gene for human lipodystrophy. Lipin defines a novel family of nuclear proteins containing at least three members in mammalian species, and homologs in distantly related organisms from human to yeast.

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Figure 1: Adipose deficiency in fld mutant mice.
Figure 2: Structure of fld and fld2J mutant alleles.
Figure 3: Lpin1 mRNA expression.
Figure 4: Evolutionary conservation of the lipin protein family and nuclear localization of lipin.

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Acknowledgements

We thank L. Rowe and the late E. Birkenmeier for a set of (BALB/c-fld×CAST)F2 DNA samples; T. Beischlag for the Arnt-GFP construct; B. Slavin for adipose tissue sections; Q. Han for assistance in the cell culture; and D. Scott for assistance with fluorescence microscopy. This work was supported by grant HL24841 from the National Institutes of Health.

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Correspondence to Karen Reue.

Supplementary information

Figure A

Alignments of the NLIP and CLIP domains showing positions of residues that are identical (black background) or similar (gray background) in at least 90% of the sequences. The asterisk above the NLIP sequence denotes the position of the Gly84Arg mutation in fld2J mice. (PPT 392 kb)

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Péterfy, M., Phan, J., Xu, P. et al. Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin. Nat Genet 27, 121–124 (2001) doi:10.1038/83685

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