Clinical and molecular characterization of a novel PLIN1 frameshift mutation identified in patients with familial partial lipodystrophy.

Autor:	Kozusko K; University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, UK., Tsang V; CSIR-IGIB, Sukhdev Vihar, Mathura Road, New Delhi, India., Bottomley W; Wellcome Trust Sanger Institute, Hinxton, University of Cambridge, UK., Cho YH; Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Australia.; Discipline of Paediatrics and Child Health, University of Sydney, Australia., Gandotra S; CSIR-IGIB, Sukhdev Vihar, Mathura Road, New Delhi, India., Mimmack ML; University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, UK., Lim K; University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, UK., Isaac I; University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, UK., Patel S; University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, UK., Saudek V; University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, UK., O'Rahilly S; University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, UK., Srinivasan S; Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Australia., Greenfield JR; Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia.; Diabetes Centre and Department of Endocrinology, St Vincent's Hospital, Sydney, Australia., Barroso I; Wellcome Trust Sanger Institute, Hinxton, University of Cambridge, UK., Campbell LV; Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Sydney, Australia.; Diabetes Centre and Department of Endocrinology, St Vincent's Hospital, Sydney, Australia., Savage DB; University of Cambridge Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, UK.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2015 Jan; Vol. 64 (1), pp. 299-310. Date of Electronic Publication: 2014 Aug 11.
DOI:	10.2337/db14-0104
Abstrakt:	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. (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)
Databáze:	MEDLINE
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