AKT2-related familial partial lipodystrophy

Summary

AKT2-related familial partial lipodystrophy (MONDO:0019192) is a disease caused by AKT2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: AKT2 (GenCC Strong)
• Cohort genes: 1
• Phenotypes (HPO): 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0000855	Insulin resistance	Obligate (100%)
HP:0009125	Lipodystrophy	Obligate (100%)
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:0003292	Decreased serum leptin	Very frequent (80-99%)
HP:0008993	Increased intraabdominal fat	Very frequent (80-99%)
HP:0030685	Decreased adiponectin level	Very frequent (80-99%)
HP:0000147	Polycystic ovaries	Frequent (30-79%)
HP:0000831	Insulin-resistant diabetes mellitus	Frequent (30-79%)
HP:0000876	Oligomenorrhea	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	AKT2-related familial partial lipodystrophy
Mondo ID	MONDO:0019192
Orphanet	79085
UMLS	C5680134
MedGen	1810936
GARD	0012599
Is cancer (heuristic)	no

Also known as: AKT2-related FPLD · familial partial lipodystrophy due to AKT2 mutations

Data availability: 2 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 › AKT2-related familial partial lipodystrophy

Related subtypes (9): familial partial lipodystrophy, Dunnigan type, PPARG-related familial partial lipodystrophy, 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, 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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · 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
AKT2	Strong	Autosomal dominant	AKT2-related familial partial lipodystrophy	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AKT2	Orphanet:293964	Hypoinsulinemic hypoglycemia and body hemihypertrophy
AKT2	Orphanet:79085	AKT2-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
AKT2	HGNC:392	ENSG00000105221	P31751	RAC-beta serine/threonine-protein kinase	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AKT2	RAC-beta serine/threonine-protein kinase	Serine/threonine kinase closely related to AKT1 and AKT3.

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AKT2	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, PH_domain

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right hemisphere of cerebellum	1
right lobe of thyroid gland	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AKT2	272	ubiquitous	marker	right uterine tube, right hemisphere of cerebellum, right lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AKT2	4,122

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AKT2	P31751	19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 98. 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
PKB-mediated events	1	11420.0×	0.007	AKT2
PDE3B signalling	1	5710.0×	0.007	AKT2
AKT-mediated inactivation of FOXO1A	1	2855.0×	0.007	AKT2
Activation of AKT2	1	2284.0×	0.007	AKT2
Inhibition of TSC complex formation by AKT (PKB)	1	2284.0×	0.007	AKT2
G-protein beta:gamma signalling	1	1903.3×	0.007	AKT2
IGF1R signaling cascade	1	1427.5×	0.007	AKT2
RUNX2 regulates genes involved in cell migration	1	1427.5×	0.007	AKT2
AKT phosphorylates targets in the nucleus	1	1142.0×	0.007	AKT2
IRS-mediated signalling	1	1038.2×	0.007	AKT2
IRS-related events triggered by IGF1R	1	1038.2×	0.007	AKT2
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	1	951.7×	0.007	AKT2
Regulation of localization of FOXO transcription factors	1	951.7×	0.007	AKT2
Signaling by Insulin receptor	1	878.5×	0.007	AKT2
SARS-CoV-2 targets host intracellular signalling and regulatory pathways	1	878.5×	0.007	AKT2
Downregulation of ERBB2:ERBB3 signaling	1	815.7×	0.007	AKT2
AKT phosphorylates targets in the cytosol	1	815.7×	0.007	AKT2
Regulation of TP53 Activity through Association with Co-factors	1	815.7×	0.007	AKT2
Activation of BAD and translocation to mitochondria	1	761.3×	0.007	AKT2
Regulation of beta-cell development	1	713.8×	0.007	AKT2
Insulin receptor signalling cascade	1	671.8×	0.007	AKT2
Regulation of gene expression in beta cells	1	519.1×	0.007	AKT2
Co-inhibition by CTLA4	1	519.1×	0.007	AKT2
Regulation of TP53 Expression and Degradation	1	519.1×	0.007	AKT2
Activation of BH3-only proteins	1	496.5×	0.007	AKT2
Regulation of TP53 Activity through Acetylation	1	456.8×	0.007	AKT2
G beta:gamma signalling through PI3Kgamma	1	439.2×	0.007	AKT2
Estrogen-dependent nuclear events downstream of ESR-membrane signaling	1	439.2×	0.007	AKT2
Regulation of T cell activation by CD28 family	1	423.0×	0.007	AKT2
Constitutive Signaling by AKT1 E17K in Cancer	1	423.0×	0.007	AKT2

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
retinal rod cell apoptotic process	1	8426.0×	0.002	AKT2
cellular response to high light intensity	1	5617.3×	0.002	AKT2
positive regulation of cap-dependent translational initiation	1	5617.3×	0.002	AKT2
negative regulation of long-chain fatty acid import across plasma membrane	1	4213.0×	0.002	AKT2
positive regulation of glucose metabolic process	1	2407.4×	0.002	AKT2
positive regulation of fatty acid beta-oxidation	1	1532.0×	0.002	AKT2
peripheral nervous system myelin maintenance	1	1532.0×	0.002	AKT2
negative regulation of PERK-mediated unfolded protein response	1	1404.3×	0.002	AKT2
mammary gland epithelial cell differentiation	1	1203.7×	0.003	AKT2
positive regulation of glycogen biosynthetic process	1	991.3×	0.003	AKT2
glycogen biosynthetic process	1	936.2×	0.003	AKT2
positive regulation of cell motility	1	766.0×	0.003	AKT2
positive regulation of protein targeting to membrane	1	561.7×	0.004	AKT2
positive regulation of D-glucose import across plasma membrane	1	455.5×	0.004	AKT2
positive regulation of blood vessel endothelial cell migration	1	391.9×	0.005	AKT2
glucose metabolic process	1	255.3×	0.007	AKT2
protein modification process	1	244.2×	0.007	AKT2
insulin receptor signaling pathway	1	221.7×	0.007	AKT2
fat cell differentiation	1	181.2×	0.008	AKT2
cellular response to insulin stimulus	1	170.2×	0.008	AKT2
regulation of cell migration	1	157.5×	0.008	AKT2
protein localization to plasma membrane	1	108.7×	0.012	AKT2
regulation of cell cycle	1	74.6×	0.016	AKT2
protein stabilization	1	66.9×	0.017	AKT2
positive regulation of cell migration	1	61.7×	0.018	AKT2
intracellular signal transduction	1	38.1×	0.028	AKT2
negative regulation of apoptotic process	1	34.8×	0.030	AKT2
signal transduction	1	16.1×	0.062	AKT2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
AKT2	CAPIVASERTIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AKT2	16	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CAPIVASERTIB	4	AKT2
SUNITINIB	4	AKT2
MIDOSTAURIN	4	AKT2
IPATASERTIB	3	AKT2
AFURESERTIB	3	AKT2
LESTAURTINIB	3	AKT2
RUBOXISTAURIN	3	AKT2
MIRANSERTIB	2	AKT2
MK-2206	2	AKT2
LAUROGUADINE	2	AKT2
UPROSERTIB	2	AKT2
SOTRASTAURIN	2	AKT2
AT-13148	1	AKT2
GSK-690693	1	AKT2
BAY-1125976	1	AKT2
VEVORISERTIB	1	AKT2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
AKT2	822	Binding:802, Functional:19, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AKT2	2.7.11.1	non-specific serine/threonine protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
AKT2	822

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

16 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)
CAPIVASERTIB	4	AKT2
SUNITINIB	4	AKT2
MIDOSTAURIN	4	AKT2
IPATASERTIB	3	AKT2
AFURESERTIB	3	AKT2
LESTAURTINIB	3	AKT2
RUBOXISTAURIN	3	AKT2
MIRANSERTIB	2	AKT2
MK-2206	2	AKT2
LAUROGUADINE	2	AKT2
UPROSERTIB	2	AKT2
SOTRASTAURIN	2	AKT2
AT-13148	1	AKT2
GSK-690693	1	AKT2
BAY-1125976	1	AKT2
VEVORISERTIB	1	AKT2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	AKT2
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.