Monogenic diabetesGene: PLIN1
Heterozygous PLIN1 frameshift mutations have been reported in patients with lipodystrophy, dyslipidaemia and severe insulin resistance: PMID:21345103; 5 patients from three families reported with PLIN1 frameshift mutations and lipodystrophy, dyslipidaemia and severe insulin resistance. Variants co-segregated with disease in two families. Patients had small adipocytes with inflammation. Mutant proteins failed to accumulate triglycerides in affected adipocytes in vitro. PMID:25114292; Pathogenic frameshift mutation identified in six patients from two families affected with lipodystrophy, severe dyslipidaemia, insulin resistance and diabetes. Variant co-segregated with disease in both pedigrees. Mutation results in reduced expression of protein, smaller lipid droplets and fails to inhibit basal lipolysis. PMID:29747582; Pathogenic frameshift mutation identified in a patient with FSGS, severe dyslipidaemia, insulin resistance, diabetes and subtle lipodystrophy. Variant also present in mother who had dyslipidaemia and diabetes. Maternal family history of dyslipidaemia, diabetes and fatty liver disease. o Heterozygous null variants predicted to undergo NMD were identified in 6 patients that did not have a PLIN1-related phenotype (PMID:30020498). PLIN1 null variants occur too frequently in gnomAD (1 in 1100) to be a cause of rare overt monogenic partial lipodystrophy. Haploinsufficiency is therefore not a pathogenic mechanism by which PLIN1 mutations cause disease, and a dominant negative/gain of function mechanism is required. All frameshift mutations reported in the literature as pathogenic are predicted to escape NMD and generate a novel protein with dominant negative effect. Therefore null variants generating PTCs that are predicted to undergo nonsense mediated decay will not be causes of monogenic disease and should not be reported as such. Adipose tissue mass in PLIN1 null mice is reduced to ~30% of that in wild-type animals. Isolated adipocytes of PLIN1 null mice exhibit elevated basal lipolysis because of the loss of the protective function of perilipin. They also exhibit dramatically attenuated stimulated lipolytic activity, indicating that perilipin is required for maximal lipolytic activity. They have a greater lean body mass and increased metabolic rate but they also show an increased tendency to develop glucose intolerance and peripheral insulin resistance (PMID: 11371650). Adipogenic signalling is dysregulated in PLIN1 null mice, with aberrant lipid droplet growth and differentiation (PMID:25695774).
Created: 15 Feb 2019, 10:28 a.m.
Comment on list classification: Promoted from amber to green as advised via email communication with Jane Houghton (South West GLH).
Created: 28 Jan 2019, 9:41 a.m.
Initial gene list and info collated by Sian Ellard, University of Exeter Medical School, August 2018 on behalf of the GMS Endocrinology specialist test group. Gene Symbol submitted: PLIN1; Suggested intial gene rating: Green; Evidence for inclusion: none given; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given; Phenotypes: Severe insulin resistance, partial lipodystrophy and diabetes.
Created: 11 Jan 2019, 10:04 a.m.
Comment on list classification: This gene was downgraded from Green to Amber due to the findings of PMID: 30020498 - variants in this gene predicted to cause haplosufficiency are not a cause of familial partial lipodystrophy.
Created: 20 Dec 2018, 5:45 p.m.
Comment on list classification: Gene added to the panel as green due to expert review.
Created: 15 Jun 2016, 3:31 p.m.
Phenotypes for gene: PLIN1 were changed from partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes; Lipodystrophy, familial partial, type 4, 613877 to partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes; Lipodystrophy, familial partial, type 4, 613877; Severe insulin resistance, partial lipodystrophy and diabetes
Publications for gene: PLIN1 were set to 21345103; 30020498
Louise Daugherty: Comment on list classification
Gene: plin1 has been classified as Green List (High Evidence).
Source NHS GMS was added to PLIN1.
Publications for gene: PLIN1 were set to 21345103
Gene: plin1 has been classified as Amber List (Moderate Evidence).
Added phenotypes partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes for gene: PLIN1
Added phenotypes partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes for gene: PLIN1 Publications for gene PLIN1 were changed from 21345103; 25114292 to 21345103
gene: PLIN1 was added gene: PLIN1 was added to Monogenic diabetes. Sources: Expert Review Green Mode of inheritance for gene: PLIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PLIN1 were set to 21345103; 25114292 Phenotypes for gene: PLIN1 were set to Lipodystrophy, familial partial, type 4, 613877