LIPE-related familial partial lipodystrophy

Summary

LIPE-related familial partial lipodystrophy (MONDO:0014431) is a disease caused by LIPE (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LIPE (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 12
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0000468	Increased adipose tissue around the neck	Obligate (100%)
HP:0000855	Insulin resistance	Obligate (100%)
HP:0003635	Loss of subcutaneous adipose tissue in limbs	Obligate (100%)
HP:0009125	Lipodystrophy	Obligate (100%)
HP:0000147	Polycystic ovaries	Very frequent (80-99%)
HP:0000831	Insulin-resistant diabetes mellitus	Very frequent (80-99%)
HP:0000876	Oligomenorrhea	Very frequent (80-99%)
HP:0000956	Acanthosis nigricans	Very frequent (80-99%)
HP:0001397	Hepatic steatosis	Very frequent (80-99%)
HP:0002155	Hypertriglyceridemia	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0003236	Elevated circulating creatine kinase concentration	Very frequent (80-99%)
HP:0003292	Decreased serum leptin	Very frequent (80-99%)
HP:0003712	Skeletal muscle hypertrophy	Very frequent (80-99%)
HP:0008993	Increased intraabdominal fat	Very frequent (80-99%)
HP:0009017	Loss of gluteal subcutaneous adipose tissue	Very frequent (80-99%)
HP:0012881	Abnormality of the labia majora	Very frequent (80-99%)
HP:0030685	Decreased adiponectin level	Very frequent (80-99%)
HP:0008994	Proximal muscle weakness in lower limbs	Frequent (30-79%)
HP:0008997	Proximal muscle weakness in upper limbs	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	LIPE-related familial partial lipodystrophy
Mondo ID	MONDO:0014431
OMIM	615980
Orphanet	435660
DOID	DOID:0070206
UMLS	C4014869
MedGen	863306
GARD	0013126
Is cancer (heuristic)	no

Also known as: FPLD6 · LIPE-related FPLD · lipodystrophy, familial partial, type 6

Data availability: 12 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › abdominal obesity-metabolic syndrome › LIPE-related familial partial lipodystrophy

Related subtypes (4): metabolic syndrome X, abdominal obesity-metabolic syndrome quantitative trait locus 2, abdominal obesity-metabolic syndrome 3, abdominal obesity-metabolic syndrome 4

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

12 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 3 likely pathogenic, 2 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
180647	NM_005357.4(LIPE):c.1519_1520dup (p.Ser508fs)	LIPE	Pathogenic	no assertion criteria provided
1028370	NM_005357.4(LIPE):c.2152C>T (p.Arg718Ter)	LIPE	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4845693	NM_005357.4(LIPE):c.232C>T (p.Gln78Ter)	LIPE	Likely pathogenic	criteria provided, single submitter
522594	NM_005357.4(LIPE):c.3103G>T (p.Glu1035Ter)	LOC101930071	Likely pathogenic	criteria provided, single submitter
155901	NM_005357.4(LIPE):c.3203_3221del (p.Val1068fs)	LIPE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
781488	NM_005357.4(LIPE):c.551C>A (p.Ser184Ter)	LIPE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2433462	NM_005357.4(LIPE):c.2461C>T (p.Arg821Cys)	LIPE	Uncertain significance	criteria provided, multiple submitters, no conflicts
3236616	NM_005357.4(LIPE):c.3079C>A (p.Leu1027Met)	LIPE	Uncertain significance	criteria provided, multiple submitters, no conflicts
3367084	NM_005357.4(LIPE):c.3212G>C (p.Gly1071Ala)	LIPE	Uncertain significance	criteria provided, single submitter
393280	NM_005357.4(LIPE):c.3040G>A (p.Val1014Met)	LIPE	Uncertain significance	criteria provided, multiple submitters, no conflicts
4079201	NM_005357.4(LIPE):c.3203_3221dup (p.His1076fs)	LIPE	Uncertain significance	criteria provided, single submitter
998371	NM_005357.4(LIPE):c.913C>T (p.Arg305Cys)	LIPE	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 1 · 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
LIPE	Strong	Autosomal recessive	LIPE-related familial partial lipodystrophy	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LIPE	Orphanet:435660	LIPE-related familial partial lipodystrophy

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LIPE	HGNC:6621	ENSG00000079435	Q05469	Hormone-sensitive lipase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LIPE	Hormone-sensitive lipase	Lipase with broad substrate specificity, catalyzing the hydrolysis of triacylglycerols (TAGs), diacylglycerols (DAGs), monoacylglycerols (MAGs), cholesteryl esters and retinyl esters.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LIPE	Enzyme (other)	yes	3.1.1.79	Lipase_GDXG_HIS_AS, HSL_N, AB_hydrolase_3

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
omental fat pad	1
peritoneum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LIPE	207	ubiquitous	yes	omental fat pad, peritoneum, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LIPE	2,583

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LIPE	Q05469	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 1 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
Triglyceride metabolism	1	671.8×	0.011	LIPE
Triglyceride catabolism	1	475.8×	0.011	LIPE
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	215.5×	0.013	LIPE
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	196.9×	0.013	LIPE
Epigenetic regulation by WDR5-containing histone modifying complexes	1	154.3×	0.013	LIPE
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	82.8×	0.020	LIPE
Epigenetic regulation of gene expression	1	71.4×	0.020	LIPE
Metabolism of lipids	1	31.6×	0.040	LIPE
Gene expression (Transcription)	1	17.8×	0.062	LIPE
Metabolism	1	11.6×	0.086	LIPE

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
diacylglycerol catabolic process	1	2808.7×	0.001	LIPE
ether lipid metabolic process	1	2808.7×	0.001	LIPE
triglyceride catabolic process	1	802.5×	0.002	LIPE
lipid catabolic process	1	244.2×	0.006	LIPE
cholesterol metabolic process	1	195.9×	0.006	LIPE
protein phosphorylation	1	68.0×	0.015	LIPE

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LIPE	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
LIPE	27	Binding:25, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LIPE	3.1.1.79	hormone-sensitive lipase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

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

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)
LIPE	27	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.