Familial diabetes

Gene: PLIN1

Green List (high evidence)

PLIN1 (perilipin 1)
EnsemblGeneIds (GRCh38): ENSG00000166819
EnsemblGeneIds (GRCh37): ENSG00000166819
OMIM: 170290, Gene2Phenotype
PLIN1 is in 5 panels

5 reviews

Jayne Houghton (Royal Devon and Exeter Foundation Trust)

Green List (high evidence)

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.

Publications

Ivone Leong (Genomics England Curator)

Green List (high evidence)

Comment on list classification: Promoted from amber to green based on the new evidence provided by Jayne Houghton (Royal Devon and Exeter Foundation Trust).
Created: 1 Mar 2019, 2:15 p.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.

Louise Daugherty (Genomics England Curator)

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, 5:48 p.m.

Sian Ellard (University of Exeter Medical School)

Green List (high evidence)

Ellen McDonagh (Genomics England Curator)

Comment on list classification: Gene added to the panel as green due to expert review.
Created: 15 Jun 2016, 3:31 p.m.

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • NHS GMS
Phenotypes
  • partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes
OMIM
170290
Clinvar variants
Variants in PLIN1
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

1 Mar 2019, Gel status: 3

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: plin1 has been classified as Green List (High Evidence).

1 Mar 2019, Gel status: 2

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: PLIN1 were set to 21345103; 30020498

20 Dec 2018, Gel status: 2

Set publications

Louise Daugherty (Genomics England Curator)

Publications for gene: PLIN1 were set to 21345103

20 Dec 2018, Gel status: 2

Entity classified by Genomics England curator

Louise Daugherty (Genomics England Curator)

Gene: plin1 has been classified as Amber List (Moderate Evidence).

28 Jun 2016, Gel status: 4

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

28 Jun 2016, Gel status: 4

Set Phenotypes

Ellen McDonagh (Genomics England Curator)

Phenotypes for PLIN1 were set to partial lipodystrophy, severe dyslipidemia, and insulin-resistant diabetes

15 Jun 2016, Gel status: 4

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

16 Oct 2015, Gel status: 0

Added New Source

Sian Ellard (University of Exeter Medical School)

PLIN1 was added to Familial diabetespanel. Sources: Expert Review