PLIN1

protein-coding

perilipin 1, the group of Perilipins

Gene summary

The protein encoded by this gene coats lipid storage droplets in adipocytes, thereby protecting them until they can be broken down by hormone-sensitive lipase. The encoded protein is the major cAMP-dependent protein kinase substrate in adipocytes and, when unphosphorylated, may play a role in the inhibition of lipolysis. Alternatively spliced transcript variants varying in the 5' UTR, but encoding the same protein, have been found for this gene. [provided by RefSeq, Feb 2009]

Previous symbols:

PLIN

MANE transcript

NM_002666.5

Inheritance

ClinVar variants

P:8U:129B:48

Top phenotype

Lipodystrophy, familial partial, type 4

gnomAD constraint

pLI —, LoF o/e 0.85

Max pathogenic AF

—

Genomic locus

chr15:89,664,367-89,679,427

External References & Databases

Ensembl (ENSG00000166819)

Transcript & Mutation Effects

hg38 • Region Span ~15.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

PLIN1-related familial partial lipodystrophyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013478

Submitter: ClinGen

*PLIN1* (previously known as *PERI*; *PLIN*; *FPLD4*) was first reported in relation to autosomal dominant familial partial lipodystrophy (FPLD4, OMIM: 613877) in 2011 (Gandotra et al., PMID: 21345103). The authors described 3 families with familial partial lipodystrophy, insulin resistance, hepatic steatosis, and dyslipidemia that cosegregates with 2 different heterozygous PLIN1 mutations [c.1210-1G > T (p.Leu404Alafs) and c.1191_1192delAG (p.Val398Glyfs)], leading to elongated perilipin 1. Typically, FPLD4 patients are characterized by lipoatrophy predominantly affecting the gluteal region and lower limbs, muscular hypertrophy, most notable on the lower limbs and no lipodystrophy in face and neck. Insulin-resistant diabetes mellitus, polycystic ovary syndrome, acanthosis nigricans, hypertriglyceridemia, hypertension, and hepatic steatosis are also present (Gandorta et al., PMID: 21345103; Kozusko et al., PMID: 25114292; Chen et al., PMID: 29747582). Renal disease has been reported once (Chen et al., PMID: 29747582). At least 5 frame shifting variants that result in the inclusion of aberrant C-terminal amino acids (125-166 amino acids) have been reported in cases of FPLD4, namely c.1191_1192del (p.Val398Glyfs; PMIDs: 21345103, 31504636), c.1201_1202dup (p.Val402Thrfs, PMID: 29747582), c.1202_1205dup (p.Pro403Argfs; PMID: 31504636), c.1308_1309del (p.Pro439Valfs; PMID: 25114292) and c.1210-1G-T (p.Leu404Alafs; PMID: 21345103) in at least 10 probands in different publications (PMIDs: 21345103; 25114292; 29747582; 31504636). Of note, histological examination of subcutaneous adipose tissue from patients revealed a significant decrease in adipocyte size, macrophage infiltration, and increased fibrosis (PMID: 21345103). For the purpose of this curation, all 10 probands are included. *Heterozygous null variants predicted to undergo nonsense-mediated decay (NMD) are relatively frequent in the population and clinical datasets and are not associated with FPLD4, thus indicating that haploinsufficiency is not a disease mechanism PLIN1-related lipodystrophy (Laver et al., PMID: 30020498, Koprulu et al. PMID: 34875679, Patel et al., PMID: 35235652); rather, it is associated with a favorable lipid profile. *Instead, the disorder results specifically from dominant-negative effects of C-terminal elongating frameshift variants predicted to escape NMD. Mechanistic studies suggest that subcutaneous patients’ adipose tissues show reduced full-length perilipin-1 and an extended perilipin-1 form compatible with the predicted elongated C-terminal tail of the mutant proteins (PMIDs: 21345103; 25114292; 31504636). Patients’ adipose tissues are also characterized by smaller adipocytes, increased macrophage infiltration and fibrosis (PMIDs: 21345103; 31504636). All but one (i.e. (p.Pro439Valfs; PMID:25114292) FPLD4-associated *PLIN1* variants [p.(Val398Glyfs), p.(Pro403Argfs), p.(Leu404Alafs)] alter the interaction domain of perilipin-1 with ABHD5 (PMIDs: 21757733; 31504636). Consistently, the p.(Val398Glyfs) and p.(Leu404Alafs) mutants fail to interact with ABHD5, leading to constitutive activation of adipocyte triglyceride lipase (PMIDs: 21345103). Although the p.(Pro439Valfs) mutant binds ABHD5, it fails to inhibit basal lipolysis probably by an alternate still unknown mechanism (PMID:25114292). *Plin1* homozygous knockout mice display a significant reduction in adipose tissue mass, approximately 30% of that observed in wild-type counterpart. Their Isolated adipocytes show elevated basal lipolysis because of the loss of the protective function of perilipin. In addition, these adipocytes show markedly reduced stimulated lipolytic activity, thus suggesting that perilipin is essential for maximal lipolysis. *Plin1* homozygous knockout mice also exhibit greater lean body mass, elevated metabolic rates, and are more prone to glucose intolerance and peripheral insulin resistance (Tansey et al., PMID: 11371650). Furthermore, adipogenic signaling is disrupted in these mice, resulting in abnormal lipid droplet growth and differentiation (Lyu et al., PMID:25695774, Patel et al., PMID: 35235652). Heterozygous knockout mice have a non-significantly lower fat mass. Experimental evidence: 6 points. Total evidence: 18 points. In summary, there is definitive evidence supporting the relationship between *PLIN1* and autosomal dominant familial partial lipodystrophy (FPLD4, OMIM: 613877). *Only frameshift variants extending the C-terminus have to date been implicated in humans. Homozgyous null variants have not been observed in humans, and heterozgyous null variants are not associated with lipodystrophy in humans. * This classification was approved by the ClinGen Monogenic Diabetes GCEP on September 10, 2025 (Gene-Disease Clinical Validity Standard Operating Procedures (SOP) - SOP11).

PLIN1-related familial partial lipodystrophySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013478

Submitter: Labcorp Genetics (formerly Invitae)

PLIN1-related familial partial lipodystrophyNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0013478

Submitter: Ambry Genetics

PLIN1-related familial partial lipodystrophySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013478

Submitter: Genomics England PanelApp

PLIN1-related familial partial lipodystrophyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013478

Submitter: PanelApp Australia

PLIN1-related familial partial lipodystrophySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013478

Submitter: Orphanet

Clinical Genomic Database (CGD)

Lipodystrophy, familial partial, type 4AD

Manifestation: Cardiovascular; Endocrine; Gastrointestinal

Intervention: Cardiovascular; Endocrine; Gastrointestinal

Rationale: Medical treatment of factors such as diabetes, hypertension, and lipid abnormalities may be beneficial to reduce morbidity/mortality; Recognition and treatment of hypertriglyceridemia can help avoid sequelae such as acute pancreatitis

Refs: 21345103; 21757733

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PLIN1 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 142

not providedTotal: 40

PLIN1-related familial partial lipodystrophyTotal: 19

PLIN1-related disorderTotal: 17

Monogenic diabetesTotal: 12

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002666.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	25 clinvar		27
missense			114 clinvar	18 clinvar	4 clinvar	136
nonsense		1 clinvar	4 clinvar			5
start loss						0
frameshift	3 clinvar	2 clinvar	5 clinvar	1 clinvar		11
splice donor/acceptor (+/-2bp)	2 clinvar		4 clinvar			6
Total	5	3	129	44	4	185

Highest pathogenic variant AF is 0.000076929435

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002666.5	RefSeq	NP_002657.3	8	MANE Select
ENST00000300055.10	Ensembl	ENSP00000300055.5	8	MANE Select
NM_001145311.2	RefSeq	NP_001138783.1	8	Standard
ENST00000430628.2	Ensembl	ENSP00000402167.2	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Regulation of lipolysis in adipocytes - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)
Apelin signaling pathway - Homo sapiens (human)
PPAR signaling pathway - Homo sapiens (human)
Transcriptional regulation of white adipocyte differentiation

Biological Process

lipid metabolic process
lipid catabolic process

Molecular Function

lipid binding

Cellular Component

endoplasmic reticulum
lipid droplet
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000300055
Coding exons: 8
Length: 15063
Individuals with no LoFs: 125663
Homozygous LoFs: 0
Heterozygous LoFs: 85
Defined: 125748
p: 0.000338

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.930	317	274	1.16	0.0000157	3252
Missense (PolyPhen)		93	96.438	0.96435		1132
Synonymous	-1.17	134	118	1.14	0.00000729	1095
Loss of Function	0.640	18	21.2	0.850	0.00000131	221

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.00093	0.00092	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00036	0.00036	rare
South Asian	0.000065	0.000065	rare
Other	0.00085	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Modulator of adipocyte lipid metabolism. Coats lipid storage droplets to protect them from breakdown by hormone- sensitive lipase (HSL). Its absence may result in leanness. Plays a role in unilocular lipid droplet formation by activating CIDEC. Their interaction promotes lipid droplet enlargement and directional net neutral lipid transfer. May modulate lipolysis and triglyceride levels. {ECO:0000269|PubMed:23399566}.;
Disease: DISEASE: Lipodystrophy, familial partial, 4 (FPLD4) [MIM:613877]: A form of lipodystrophy characterized by loss of subcutaneous adipose tissue primarily affecting the lower limbs, insulin- resistant diabetes mellitus, hypertriglyceridemia, and hypertension. {ECO:0000269|PubMed:21345103}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.290

Intolerance Scores

LoFtool: 0.856
RVIS EVS: 0.76
RVIS percentile EVS: 86.8

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium