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The minor allele of the missense polymorphism Ser251Pro in perilipin 2 (PLIN2) disrupts an α‐helix, affects lipolysis, and is associated with reduced plasma triglyceride concentration in humans
Author(s) -
Magné Joëlle,
Aminoff Anna,
Sundelin Jeanna Perman,
Mannila Maria Nastase,
Gustafsson Peter,
Hultenby Kjell,
Wernerson Annika,
Bauer Greta,
Listenberger Laura,
Neville Matt J.,
Karpe Fredrik,
Borén Jan,
Ehrenborg Ewa
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-228759
Subject(s) - perilipin , minor allele frequency , biology , lipid droplet , allele , triglyceride , missense mutation , lipolysis , transfection , endocrinology , medicine , genetics , adipose tissue , cholesterol , microbiology and biotechnology , cell culture , allele frequency , gene , phenotype
Perilipin 2 (PLIN2) is the most abundant lipid droplet (LD)‐associated protein in nonadipose tissue, and its expression correlates with intracellular lipid accumulation. Here we identified a missense polymorphism, Ser251Pro, that has major effect on protein structure and function, along with an influence on human plasma triglyceride concentration. The evolutionarily conserved Ser251Pro polymorphism was identified with the ClustalW program. Structure modeling using 3D‐JigSaw and the Chimera package revealed that the Pro251 allele disrupts a predicted α‐helix in PLIN2. Analyses of macrophages from individuals carrying Ser251Pro variants and human embryonic kidney 293 (HEK293) cells stably transfected with either of the alleles demonstrated that the Pro251 variant causes increased lipid accumulation and decreased lipolysis. Analysis of LD size distribution in stably transfected cells showed that the minor Pro251 allele resulted in an increased number of small LDs per cell and increased perilipin 3 protein expression levels as compared with cells carrying the major Ser251 allele. Genotyping of 2113 individuals indicated that the Pro251 variant is associated with decreased plasma triglyceride and very low‐density lipoprotein concentrations. Altogether, these data provide the first evidence of a polymorphism in PLIN2 that affects PLIN2 function and may influence the development of metabolic and cardiovascular diseases.—Magné, J., Aminoff, A., Perman Sundelin, J., Mannila, M. N., Gustafsson, P., Hultenby, K., Wernerson, A., Bauer, G., Listenberger, L., Neville, M. J., Karpe, F., Borén, J., Ehrenborg, E., The minor allele of the missense polymorphism Ser251Pro in perilipin 2 (PLIN2) disrupts an α‐helix, affects lipolysis, and is associated with reduced plasma triglyceride concentration in humans. FASEB J. 27, 3090–3099 (2013). www.fasebj.org