PPARG-related familial partial lipodystrophy

Summary

PPARG-related familial partial lipodystrophy (MONDO:0011448) is a disease caused by PPARG (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PPARG (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 57
• Phenotypes (HPO): 36

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0000822	Hypertension	Obligate (100%)
HP:0000855	Insulin resistance	Obligate (100%)
HP:0100578	Lipoatrophy	Obligate (100%)
HP:0000819	Diabetes mellitus	Very frequent (80-99%)
HP:0000831	Insulin-resistant diabetes mellitus	Very frequent (80-99%)
HP:0000991	Xanthomatosis	Very frequent (80-99%)
HP:0002155	Hypertriglyceridemia	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0003635	Loss of subcutaneous adipose tissue in limbs	Very frequent (80-99%)
HP:0008065	Aplasia/Hypoplasia of the skin	Very frequent (80-99%)
HP:0000869	Secondary amenorrhea	Frequent (30-79%)
HP:0000963	Thin skin	Frequent (30-79%)
HP:0002621	Atherosclerosis	Frequent (30-79%)
HP:0003712	Skeletal muscle hypertrophy	Frequent (30-79%)
HP:0000147	Polycystic ovaries	Occasional (5-29%)
HP:0000292	Loss of facial adipose tissue	Occasional (5-29%)
HP:0000876	Oligomenorrhea	Occasional (5-29%)
HP:0000956	Acanthosis nigricans	Occasional (5-29%)
HP:0001397	Hepatic steatosis	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0001639	Hypertrophic cardiomyopathy	Occasional (5-29%)
HP:0001677	Coronaryartery atherosclerosis	Occasional (5-29%)
HP:0001733	Pancreatitis	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0002149	Hyperuricemia	Occasional (5-29%)
HP:0002230	Generalized hirsutism	Occasional (5-29%)
HP:0003198	Myopathy	Occasional (5-29%)
HP:0003326	Myalgia	Occasional (5-29%)
HP:0003707	Calf muscle pseudohypertrophy	Occasional (5-29%)
HP:0009800	Maternal diabetes	Occasional (5-29%)
HP:0012084	Abnormality of skeletal muscle fiber size	Occasional (5-29%)
HP:0100601	Eclampsia	Occasional (5-29%)
HP:0100607	Dysmenorrhea	Occasional (5-29%)
HP:0000786	Primary amenorrhea	Very rare (<1-4%)
HP:0001394	Cirrhosis	Very rare (<1-4%)
HP:0007457	Prominent veins on trunk	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	PPARG-related familial partial lipodystrophy
Mondo ID	MONDO:0011448
OMIM	604367
Orphanet	79083
DOID	DOID:0070204
UMLS	C1720861
MedGen	328393
GARD	0012600
Is cancer (heuristic)	no

Also known as: familial partial lipodystrophy associated with PPARG mutations · familial partial lipodystrophy type 3 · FPLD3 · lipodystrophy, familial partial, type 3 · PPARG-related FPLD

Data availability: 57 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › lipodystrophy › hereditary lipodystrophy › familial partial lipodystrophy › PPARG-related familial partial lipodystrophy

Related subtypes (9): familial partial lipodystrophy, Dunnigan type, familial partial lipodystrophy, Kobberling type, PLIN1-related familial partial lipodystrophy, CIDEC-related familial partial lipodystrophy, LIPE-related familial partial lipodystrophy, autosomal semi-dominant severe lipodystrophic laminopathy, AKT2-related familial partial lipodystrophy, lipodystrophy, familial partial, type 8, lipodystrophy, familial partial, type 9

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

57 retrieved; paginated sample, class counts are floors:

13 likely pathogenic, 13 uncertain significance, 12 pathogenic, 9 conflicting classifications of pathogenicity, 5 benign/likely benign, 3 pathogenic/likely pathogenic, 1 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3024551	NM_138711.6(PPARG):c.551C>T (p.Pro184Leu)	LOC114803475	Pathogenic	no assertion criteria provided
4277380	Single allele	LOC129936169	Pathogenic	criteria provided, single submitter
1070305	NM_138711.6(PPARG):c.362A>G (p.Tyr121Cys)	PPARG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1285541	NM_138711.6(PPARG):c.530-1G>A	PPARG	Pathogenic	criteria provided, single submitter
2412803	NM_138711.6(PPARG):c.258T>G (p.Tyr86Ter)	PPARG	Pathogenic	criteria provided, single submitter
3024550	NM_138711.6(PPARG):c.443T>C (p.Leu148Pro)	PPARG	Pathogenic	no assertion criteria provided
3358997	NM_138711.6(PPARG):c.221-1G>C	PPARG	Pathogenic	criteria provided, single submitter
436400	NM_138711.6(PPARG):c.924_928del (p.Asp308fs)	PPARG	Pathogenic	criteria provided, single submitter
436405	NM_138711.6(PPARG):c.1271del (p.Pro424fs)	PPARG	Pathogenic	criteria provided, multiple submitters, no conflicts
8136	NM_138711.6(PPARG):c.1394C>T (p.Pro465Leu)	PPARG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8137	NM_138711.6(PPARG):c.862G>A (p.Val288Met)	PPARG	Pathogenic	no assertion criteria provided
8141	NM_138711.6(PPARG):c.1074T>A (p.Phe358Leu)	PPARG	Pathogenic	no assertion criteria provided
8142	NM_138711.6(PPARG):c.1183C>T (p.Arg395Cys)	PPARG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8143	NM_138711.6(PPARG):c.478T>A (p.Cys160Ser)	PPARG	Pathogenic	no assertion criteria provided
8144	NM_138711.6(PPARG):c.490C>T (p.Arg164Trp)	PPARG	Pathogenic	no assertion criteria provided
1341522	NM_138711.6(PPARG):c.544C>T (p.Arg182Trp)	LOC114803475	Likely pathogenic	criteria provided, multiple submitters, no conflicts
976149	NM_138711.6(PPARG):c.614_616delinsC (p.Glu205fs)	LOC114803475	Likely pathogenic	criteria provided, single submitter
1098721	NM_138711.6(PPARG):c.353G>A (p.Gly118Glu)	PPARG	Likely pathogenic	criteria provided, single submitter
1341578	NM_138711.6(PPARG):c.1124T>C (p.Leu375Pro)	PPARG	Likely pathogenic	criteria provided, single submitter
1676242	NM_138711.6(PPARG):c.841C>T (p.Gln281Ter)	PPARG	Likely pathogenic	criteria provided, single submitter
3340491	NM_138711.6(PPARG):c.346dup (p.Ala116fs)	PPARG	Likely pathogenic	criteria provided, single submitter
436397	NM_138711.6(PPARG):c.491G>A (p.Arg164Gln)	PPARG	Likely pathogenic	criteria provided, multiple submitters, no conflicts
436398	NM_138711.6(PPARG):c.545G>A (p.Arg182Gln)	PPARG	Likely pathogenic	criteria provided, single submitter
436399	NM_138711.6(PPARG):c.881T>C (p.Ile294Thr)	PPARG	Likely pathogenic	criteria provided, single submitter
436404	NM_138711.6(PPARG):c.1262T>C (p.Leu421Pro)	PPARG	Likely pathogenic	criteria provided, single submitter
436406	NM_138711.6(PPARG):c.380A>G (p.Glu127Gly)	PPARG	Likely pathogenic	criteria provided, single submitter
976317	NM_138711.6(PPARG):c.629G>C (p.Arg210Pro)	PPARG	Likely pathogenic	criteria provided, single submitter
983029	NM_138711.6(PPARG):c.614_615del (p.Glu205fs)	PPARG	Likely pathogenic	criteria provided, single submitter
3345678	NM_138711.6(PPARG):c.275T>C (p.Leu92Pro)	PPARG	Conflicting classifications of pathogenicity	no assertion criteria provided
342920	NM_138711.6(PPARG):c.150C>T (p.Asp50=)	PPARG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PPARG	Definitive	Autosomal dominant	PPARG-related familial partial lipodystrophy	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PPARG	Orphanet:146	Differentiated thyroid carcinoma
PPARG	Orphanet:251576	Gliosarcoma
PPARG	Orphanet:251579	Giant cell glioblastoma
PPARG	Orphanet:696242	PPARG-associated congenital generalized lipodystrophy
PPARG	Orphanet:79083	PPARG-related familial partial lipodystrophy
BSCL2	Orphanet:100998	Autosomal dominant spastic paraplegia type 17
BSCL2	Orphanet:139536	Distal hereditary motor neuropathy type 5
BSCL2	Orphanet:363400	Progressive encephalopathy-severe neurodegeneration-lipodystrophy syndrome
BSCL2	Orphanet:696289	Congenital generalized lipodystrophy type 2

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PPARG	HGNC:9236	ENSG00000132170	P37231	Peroxisome proliferator-activated receptor gamma	gencc,clinvar
BSCL2	HGNC:15832	ENSG00000168000	Q96G97	Seipin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PPARG	Peroxisome proliferator-activated receptor gamma	Ligand-activated transcription factor that forms obligate heterodimers with the retinoic acid receptor and acts as a key regulator of biological processes, such as adipocyte differentiation, lipid metabolism, glucose homeostasis and beta-o…
BSCL2	Seipin	Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Nuclear receptor	1	192.9×	0.010
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PPARG	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
BSCL2	Other/Unknown	no		Seipin

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adipose tissue of abdominal region	1
omental fat pad	1
peritoneum	1
pituitary gland	1
primary visual cortex	1
superior frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PPARG	194	ubiquitous	marker	omental fat pad, peritoneum, adipose tissue of abdominal region
BSCL2	149	ubiquitous	marker	superior frontal gyrus, primary visual cortex, pituitary gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PPARG	7,747
BSCL2	1,503

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PPARG	P37231	380
BSCL2	Q96G97	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MECP2 regulates transcription factors	1	2284.0×	0.004	PPARG
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	1	380.7×	0.008	PPARG
SUMOylation of intracellular receptors	1	335.9×	0.008	PPARG
Nuclear Receptor transcription pathway	1	200.3×	0.009	PPARG
Regulation of PTEN gene transcription	1	178.4×	0.009	PPARG
Transcriptional regulation of white adipocyte differentiation	1	129.8×	0.010	PPARG
PPARA activates gene expression	1	94.4×	0.012	PPARG
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	82.8×	0.012	PPARG

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
fat cell differentiation	2	181.2×	0.002	PPARG, BSCL2
negative regulation of connective tissue replacement involved in inflammatory response wound healing	1	4213.0×	0.004	PPARG
positive regulation of adiponectin secretion	1	2808.7×	0.004	PPARG
beige fat cell differentiation	1	2808.7×	0.004	PPARG
negative regulation of extracellular matrix assembly	1	2106.5×	0.004	PPARG
negative regulation of cellular response to transforming growth factor beta stimulus	1	2106.5×	0.004	PPARG
positive regulation of lipid metabolic process	1	1685.2×	0.004	PPARG
positive regulation of fatty acid metabolic process	1	1685.2×	0.004	PPARG
negative regulation of mitochondrial fission	1	1685.2×	0.004	PPARG
positive regulation of lipoprotein transport	1	1685.2×	0.004	PPARG
negative regulation of receptor signaling pathway via STAT	1	1685.2×	0.004	PPARG
negative regulation of vascular endothelial cell proliferation	1	1685.2×	0.004	PPARG
positive regulation of cholesterol transport	1	1203.7×	0.005	PPARG
response to lipid	1	1203.7×	0.005	PPARG
negative regulation of type II interferon-mediated signaling pathway	1	1053.2×	0.005	PPARG
positive regulation of vascular associated smooth muscle cell apoptotic process	1	1053.2×	0.005	PPARG
negative regulation of cardiac muscle hypertrophy in response to stress	1	936.2×	0.005	PPARG
negative regulation of cholesterol storage	1	766.0×	0.005	PPARG
negative regulation of lipid storage	1	766.0×	0.005	PPARG
peroxisome proliferator activated receptor signaling pathway	1	766.0×	0.005	PPARG
regulation of cellular response to insulin stimulus	1	766.0×	0.005	PPARG
negative regulation of macrophage derived foam cell differentiation	1	648.1×	0.005	PPARG
long-chain fatty acid transport	1	561.7×	0.006	PPARG
positive regulation of adipose tissue development	1	526.6×	0.006	PPARG
intracellular receptor signaling pathway	1	495.6×	0.006	PPARG
lipid droplet formation	1	495.6×	0.006	BSCL2
lipid droplet organization	1	468.1×	0.006	BSCL2
cellular response to low-density lipoprotein particle stimulus	1	443.5×	0.006	PPARG
white fat cell differentiation	1	421.3×	0.006	PPARG
negative regulation of lipid catabolic process	1	421.3×	0.006	BSCL2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PPARG	METHYLENE BLUE ANHYDROUS

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PPARG	83	4
BSCL2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
METHYLENE BLUE ANHYDROUS	4	PPARG
BENZBROMARONE	4	PPARG
BEXAROTENE	4	PPARG
PIOGLITAZONE HYDROCHLORIDE	4	PPARG
ROSIGLITAZONE MALEATE	4	PPARG
CANDESARTAN CILEXETIL	4	PPARG
TELMISARTAN	4	PPARG
RIMONABANT	4	PPARG
CEFAMANDOLE	4	PPARG
CLOBETASOL PROPIONATE	4	PPARG
ROSIGLITAZONE	4	PPARG
FULVESTRANT	4	PPARG
LIOTHYRONINE	4	PPARG
SULINDAC	4	PPARG
CEFTRIAXONE	4	PPARG
LEVOTHYROXINE	4	PPARG
CEFOTAXIME	4	PPARG
CANNABIDIOL	4	PPARG
TIPRANAVIR	4	PPARG
EFAVIRENZ	4	PPARG
PEMAFIBRATE	4	PPARG
MASOPROCOL	4	PPARG
LASOFOXIFENE	4	PPARG
ELAFIBRANOR	4	PPARG
LUMIRACOXIB	4	PPARG
TROGLITAZONE	4	PPARG
CEFTAZIDIME	4	PPARG
GEMFIBROZIL	4	PPARG
GLYBURIDE	4	PPARG
NINTEDANIB	4	PPARG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PPARG	2,033	Binding:1593, Functional:380, ADMET:56, Toxicity:3, Unclassified:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PPARG	2,033

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
METHYLENE BLUE ANHYDROUS	4	PPARG
BENZBROMARONE	4	PPARG
BEXAROTENE	4	PPARG
PIOGLITAZONE HYDROCHLORIDE	4	PPARG
ROSIGLITAZONE MALEATE	4	PPARG
CANDESARTAN CILEXETIL	4	PPARG
TELMISARTAN	4	PPARG
RIMONABANT	4	PPARG
CEFAMANDOLE	4	PPARG
CLOBETASOL PROPIONATE	4	PPARG
ROSIGLITAZONE	4	PPARG
FULVESTRANT	4	PPARG
LIOTHYRONINE	4	PPARG
SULINDAC	4	PPARG
CEFTRIAXONE	4	PPARG
LEVOTHYROXINE	4	PPARG
CEFOTAXIME	4	PPARG
CANNABIDIOL	4	PPARG
TIPRANAVIR	4	PPARG
EFAVIRENZ	4	PPARG
PEMAFIBRATE	4	PPARG
MASOPROCOL	4	PPARG
LASOFOXIFENE	4	PPARG
ELAFIBRANOR	4	PPARG
LUMIRACOXIB	4	PPARG
TROGLITAZONE	4	PPARG
CEFTAZIDIME	4	PPARG
GEMFIBROZIL	4	PPARG
GLYBURIDE	4	PPARG
NINTEDANIB	4	PPARG

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PPARG
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	BSCL2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
BSCL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.