title: Clinical and molecular characterization of a novel PLIN1 frameshift mutation identified in patients with familial partial lipodystrophy.
abstract: Perilipin 1 is a lipid droplet coat protein predominantly expressed in adipocytes, where it inhibits basal and facilitates stimulated lipolysis. Loss-of-function mutations in the PLIN1 gene were recently reported in patients with a novel subtype of familial partial lipodystrophy, designated as FPLD4. We now report the identification and characterization of a novel heterozygous frameshift mutation affecting the carboxy-terminus (439fs) of perilipin 1 in two unrelated families. The mutation cosegregated with a similar phenotype including partial lipodystrophy, severe insulin resistance and type 2 diabetes, extreme hypertriglyceridemia, and nonalcoholic fatty liver disease in both families. Poor metabolic control despite maximal medical therapy prompted two patients to undergo bariatric surgery, with remarkably beneficial consequences. Functional studies indicated that expression levels of the mutant protein were lower than wild-type protein, and in stably transfected preadipocytes the mutant protein was associated with smaller lipid droplets. Interestingly, unlike the previously reported 398 and 404 frameshift mutants, this variant binds and stabilizes ABHD5 expression but still fails to inhibit basal lipolysis as effectively as wild-type perilipin 1. Collectively, these findings highlight the physiological need for exquisite regulation of neutral lipid storage within adipocyte lipid droplets, as well as the possible metabolic benefits of bariatric surgery in this serious disease.
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, UK.
authors.forename: K
authors.initials: K
authors.lastname: Kozusko
authors.affiliation: CSIR-IGIB, Sukhdev Vihar, Mathura Road, New Delhi, India.
authors.forename: Vhm
authors.initials: V
authors.lastname: Tsang
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, University of Cambridge, UK.
authors.forename: W
authors.initials: W
authors.lastname: Bottomley
authors.affiliation: Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Australia.|Discipline of Paediatrics and Child Health, University of Sydney, Australia.
authors.forename: Y H
authors.initials: YH
authors.lastname: Cho
authors.affiliation: CSIR-IGIB, Sukhdev Vihar, Mathura Road, New Delhi, India.
authors.forename: S
authors.initials: S
authors.lastname: Gandotra
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, UK.
authors.forename: M L
authors.initials: ML
authors.lastname: Mimmack
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, UK.
authors.forename: K
authors.initials: K
authors.lastname: Lim
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, UK.
authors.forename: I
authors.initials: I
authors.lastname: Isaac
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, UK.
authors.forename: Satish
authors.initials: S
authors.lastname: Patel
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, UK.
authors.forename: V
authors.initials: V
authors.lastname: Saudek
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, UK.
authors.forename: S
authors.initials: S
authors.lastname: O'Rahilly
authors.affiliation: Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia.|Diabetes Centre and Department of Endocrinology, St Vincent's Hospital, Sydney, Australia.
authors.forename: J R
authors.initials: JR
authors.lastname: Greenfield
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, University of Cambridge, UK.
authors.forename: I
authors.initials: I
authors.lastname: Barroso
authors.affiliation: Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia.|Diabetes Centre and Department of Endocrinology, St Vincent's Hospital, Sydney, Australia.
authors.forename: L V
authors.initials: LV
authors.lastname: Campbell
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, UK.
authors.forename: D B
authors.initials: DB
authors.lastname: Savage
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000378:metabolism; D041721:3T3-L1 Cells; D052438:Adipocytes, White / Q000502:physiology; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005192:Family Health; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D006953:Hyperlipoproteinemia Type IV / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics; D052496:Lipodystrophy, Familial Partial / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010375:Pedigree; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C000602978:PLIN1 protein, human; D000070778:Perilipin-1; D010750:Phosphoproteins; C000602979:Plin1 protein, mouse; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C439972:ABHD5 protein, human
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