PPARG
protein-codingperoxisome proliferator activated receptor gamma, the group of Peroxisome proliferator activated receptors
Gene summary
This gene encodes a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors. PPARs form heterodimers with retinoid X receptors (RXRs) and these heterodimers regulate transcription of various genes. Three subtypes of PPARs are known: PPAR-alpha, PPAR-delta, and PPAR-gamma. The protein encoded by this gene is PPAR-gamma and is a regulator of adipocyte differentiation. Additionally, PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis and cancer. Alternatively spliced transcript variants that encode different isoforms have been described. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~147.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0011448
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0011448
Submitter: G2P
Inheritance Pattern: SD
Disease ID:MONDO:0006573
Submitter: ClinGen
Human pathogenic *PPARG* variants were first reported in autosomal dominantly inherited severe insulin resistance in 1999 (Barroso et al, PMID:10622252), attributed to lipodystrophy shortly afterwards (Agarwal et al, PMID: 11788685). We have now curated the inheritance pattern for *PPARG*-related lipodystrophy as semidominant because, while most cases are autosomal dominant, very rarely a recessive mode of inheritance has been reported (Dyment et al, PMID:24980513; Gosseaume et al, PMID:36806620). Both loss of function and dominant negative variants have been reported. Typical autosomal dominant cases due to heterozygous variants present with loss of subcutaneous adipose tissue, especially of the limbs, and metabolic complications, in a form of familial partial lipodystrophy (Chen et al et al, PMID:35422762; PMID:36806620; Vasandani et al, PMID:36397776). The occasional recessive cases typically feature early-onset, congenital generalized lipodystrophy, also known as Berardinelli-Seip syndrome, due to biallelic variants in *PPARG* (PMIDs:24980513, 36806620). At least 60 lipodystrophy-causing *PPARG* variants (primarily missense) have been reported in humans. Evidence supporting the association of this gene with lipodystrophy includes case-level data, segregation data, and experimental data. **The aggregated score for case-level and segregation data is 12 points.** Variants in this gene have been reported in at least 35 probands in 14 publications (PMIDs: 17766367, 24980513, 16965332, 10622252, 17299075, 29622583, 35422762, 17011503, 12453919, 11788685, 22750678, 34168618, 36806620, 36397776), with most cases presenting as familial partial lipodystrophy and two cases with congenital, generalized lipodystrophy. More evidence is available to support the gene-disease association in the literature, but as the maximum score for genetic evidence (12 points) has been reached this has not been curated exhaustively. This gene-disease relationship is supported by functional assays (both individual and massively parallel), expression studies and functional alterations. **Total points for the experimental evidence are 4. Total points for genetic and experimental evidence together are thus 16.** Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found both differences in inheritance pattern and phenotypic variability, but also overlap in the implicated variants. Specifically, *PPARG* has two associated diseases, namely the more commonly associated autosomal dominant familial partial lipodystrophy (OMIM:604367), and the more rarely associated autosomal recessive congenital, generalized lipodystrophy. Because the latter is rare and there is overlap in the implicated variants, these two entities have been lumped in a single curation of lipodystrophy (MONDO: 0006573). In summary, *PPARG* is definitively associated with semidominant lipodystrophy, with most cases presenting as autosomal dominant familial partial lipodystrophy in adolescents and young adults. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0011448
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0011448
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011448
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0011448
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Endocrine
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PPARG variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_138711.6. 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 | 3 | 70 | 3 | 76 | ||
| missense | 7 | 17 | 154 | 5 | 1 | 184 |
| nonsense | 4 | 3 | 1 | 8 | ||
| start loss | 0 | |||||
| frameshift | 4 | 7 | 1 | 12 | ||
| splice donor/acceptor (+/-2bp) | 3 | 2 | 1 | 6 | ||
| Total | 18 | 29 | 160 | 75 | 4 | 286 |
Highest pathogenic variant AF is 0.000006572116
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_619725.3 | 6 | MANE Select | |
| Ensembl | ENSP00000498313.1 | 6 | MANE Select | |
| RefSeq | NP_001317544.2 | 5 | Standard | |
| RefSeq | NP_001341595.2 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pparg | Danio rerio | Structure: pancreatic B cell Quality: increased area abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Huntington,s disease - Homo sapiens (human)
- AMPK signaling pathway - Homo sapiens (human)
- Thermogenesis - Homo sapiens (human)
- Longevity regulating pathway - Homo sapiens (human)
- PPAR signaling pathway - Homo sapiens (human)
Biological Process
- negative regulation of transcription by RNA polymerase II
- placenta development
- negative regulation of acute inflammatory response
- regulation of transcription by RNA polymerase II
- transcription initiation from RNA polymerase II promoter
Molecular Function
- transcription regulatory region sequence-specific DNA binding
- RNA polymerase II regulatory region sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- RNA polymerase II repressing transcription factor binding
- DNA-binding transcription repressor activity, RNA polymerase II-specific
Cellular Component
- nucleus
- nucleoplasm
- cytosol
- protein-containing complex
- intracellular membrane-bounded organelle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000287820
- Coding exons
- 7
- Length
- 146989
- Individuals with no LoFs
- 125735
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 10
- Defined
- 125745
- p
- 0.0000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.12 | 183 | 283 | 0.646 | 0.0000154 | 3374 |
| Missense (PolyPhen) | 59 | 126.87 | 0.46505 | 1455 | ||
| Synonymous | -0.0556 | 109 | 108 | 1.01 | 0.00000627 | 944 |
| Loss of Function | 2.71 | 6 | 18.6 | 0.322 | 8.70e-7 | 247 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels (By similarity). {ECO:0000250|UniProtKB:P37238, ECO:0000269|PubMed:16150867, ECO:0000269|PubMed:20829347, ECO:0000269|PubMed:23525231, ECO:0000269|PubMed:9065481}.;
- Disease
- DISEASE: Note=Defects in PPARG can lead to type 2 insulin- resistant diabetes and hyptertension. PPARG mutations may be associated with colon cancer. {ECO:0000269|PubMed:10394368}.; DISEASE: Obesity (OBESITY) [MIM:601665]: A condition characterized by an increase of body weight beyond the limitation of skeletal and physical requirements, as the result of excessive accumulation of body fat. {ECO:0000269|PubMed:9753710}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry.; DISEASE: Lipodystrophy, familial partial, 3 (FPLD3) [MIM:604367]: A form of lipodystrophy characterized by marked loss of subcutaneous fat from the extremities. Facial adipose tissue may be increased, decreased or normal. Affected individuals show an increased preponderance of insulin resistance, diabetes mellitus and dyslipidemia. {ECO:0000269|PubMed:11788685, ECO:0000269|PubMed:12453919}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Glioma 1 (GLM1) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. {ECO:0000269|PubMed:10851250}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. Polymorphic PPARG alleles have been found to be significantly over-represented among a cohort of American patients with sporadic glioblastoma multiforme suggesting a possible contribution to disease susceptibility.;
Recessive Scores
- pRec
- 0.974
Intolerance Scores
- LoFtool
- 0.0635
- RVIS EVS
- -0.31
- RVIS percentile EVS
- 31.93
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- H
- Indispensability pred.
- E
- Indispensability score
- 0.999
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |