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Perilipin is the most abundant adipocyte-specific protein that coats lipid droplets, and it is required for optimal lipid incorporation and release from the droplet. We identified two heterozygous frameshift mutations in the perilipin gene (PLIN1) in three families with partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes. Subcutaneous fat from the patients was characterized by smaller-than-normal adipocytes, macrophage infiltration, and fibrosis. In contrast to wild-type perilipin, mutant forms of the protein failed to increase triglyceride accumulation when expressed heterologously in preadipocytes. These findings define a novel dominant form of inherited lipodystrophy and highlight the serious metabolic consequences of a primary defect in the formation of lipid droplets in adipose tissue.

Lipodystrophic syndromes are characterized by adipose tissue deficiency. Although rare, they are of considerable interest as they, like obesity, typically lead to ectopic lipid accumulation, dyslipidaemia and insulin resistant diabetes. In this paper we describe a female patient with partial lipodystrophy (affecting limb, femorogluteal and subcutaneous abdominal fat), white adipocytes with multiloculated lipid droplets and insulin-resistant diabetes, who was found to be homozygous for a premature truncation mutation in the lipid droplet protein cell death-inducing Dffa-like effector C (CIDEC) (E186X). The truncation disrupts the highly conserved CIDE-C domain and the mutant protein is mistargeted and fails to increase the lipid droplet size in transfected cells. In mice, Cidec deficiency also reduces fat mass and induces the formation of white adipocytes with multilocular lipid droplets, but in contrast to our patient, Cidec null mice are protected against diet-induced obesity and insulin resistance. In addition to describing a novel autosomal recessive form of familial partial lipodystrophy, these observations also suggest that CIDEC is required for unilocular lipid droplet formation and optimal energy storage in human fat.

R e s e a R c h a R t i c l e4 0 2 8 jci.org Volume 124 Number 9 September 2014 IntroductionPrimordial dwarfism denotes extreme linear growth impairment from early gestation. When severely reduced head size is also seen, primordial dwarfism is said to be microcephalic. This is generally taken to imply a global problem with either cellular or organismal growth and contrasts with primordial dwarfism in which the head size is relatively preserved, which is more likely to be accounted for by a more tissue-selective problem, affecting, for example, long bone growth (1). Many human genetic defects have now been described as underlying microcephalic primordial dwarfism. These may affect endocrine growth regulation by impairing production or action of IGF-1 (2, 3); however, most mutations reported to date affect cellautonomous growth. Some clustering of defects according to the cellular structure or process affected is apparent. For example, microcephalic primordial dwarfism can result from defects in genes involved in the licensing of DNA replication, in centrosome function, or in DNA damage response and repair pathways (reviewed in ref. 4).In keeping with the known roles of the defective genes, some syndromes feature a characteristic profile of chromosomal instability or impaired DNA damage repair. Some components of the syndromes cannot easily be explained by known functions of the affected gene, however. An example is the severe insulin resistance described in pericentrin deficiency (5). This usually appears during the first decade of life and is associated with severely fatty liver, elevated blood triglyceride levels, and diabetes, recapitulating in severe form the pandemic metabolic syndrome. Similar metabolic abnormalities are seen with milder growth impairment in both Bloom syndrome (6) and Werner syndrome (7), each caused by loss of a DNA helicase, and without growth impairment in patients with a heterozygous polymerase-inactivating mutation in DNA polymerase δ (8). However despite increasing evidence of a link between impaired DNA replication and/or damage responses and severe insulin resistance, the underlying mechanisms linking these remain unclear. ResultsA novel syndrome of primordial dwarfism. We identified 2 female patients with similar syndromes (details in Supplemental Material and Methods; supplemental material available online with this article; doi:10.1172/JCI73264DS1). The shared features are (a) severe primordial dwarfism, with facial dysmorphism, including Structural maintenance of chromosomes (SMC) complexes are essential for maintaining chromatin structure and regulating gene expression. Two the three known SMC complexes, cohesin and condensin, are important for sister chromatid cohesion and condensation, respectively; however, the function of the third complex, SMC5-6, which includes the E3 SUMO-ligase NSMCE2 (also widely known as MMS21) is less clear. Here, we characterized 2 patients with primordial dwarfism, extreme insulin resistance, and gonadal failure and identified compound heterozygou...

Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome.