mandibuloacral dysplasia with type B lipodystrophy

Summary

mandibuloacral dysplasia with type B lipodystrophy (MONDO:0012074) is a disease caused by ZMPSTE24 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ZMPSTE24 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 61
• Phenotypes (HPO): 28

Clinical features

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0000160	Narrow mouth	Very frequent (80-99%)
HP:0000239	Large fontanelles	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000924	Abnormality of the skeletal system	Very frequent (80-99%)
HP:0000963	Thin skin	Very frequent (80-99%)
HP:0001870	Acroosteolysis of distal phalanges (feet)	Very frequent (80-99%)
HP:0002797	Osteolysis	Very frequent (80-99%)
HP:0004334	Dermal atrophy	Very frequent (80-99%)
HP:0006710	Aplasia/Hypoplasia of the clavicles	Very frequent (80-99%)
HP:0009839	Osteolytic defects of the distal phalanges of the hand	Very frequent (80-99%)
HP:0009882	Short distal phalanx of finger	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000444	Convex nasal ridge	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0000855	Insulin resistance	Frequent (30-79%)
HP:0000953	Hyperpigmentation of the skin	Frequent (30-79%)
HP:0001211	Abnormal fingertip morphology	Frequent (30-79%)
HP:0001595	Abnormality of the hair	Frequent (30-79%)
HP:0001596	Alopecia	Frequent (30-79%)
HP:0003077	Hyperlipidemia	Frequent (30-79%)
HP:0003196	Short nose	Frequent (30-79%)
HP:0003761	Calcinosis	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0005328	Progeroid facial appearance	Frequent (30-79%)
HP:0007495	Prematurely aged appearance	Frequent (30-79%)
HP:0008404	Nail dystrophy	Frequent (30-79%)
HP:0009064	Generalized lipodystrophy	Frequent (30-79%)
HP:0000823	Delayed puberty	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mandibuloacral dysplasia with type B lipodystrophy
Mondo ID	MONDO:0012074
MeSH	C535706
OMIM	608612
Orphanet	90154
DOID	DOID:0081129
ICD-11	1199517264
UMLS	C1837756
MedGen	332940
GARD	0009989
Is cancer (heuristic)	no

Also known as: MADB · mandibuloacral dysplasia with type B lipodystrophy

Data availability: 61 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › multiple congenital anomalies/dysmorphic syndrome › multiple congenital anomalies/dysmorphic syndrome without intellectual disability › mandibuloacral dysplasia › mandibuloacral dysplasia with type B lipodystrophy

Related subtypes (1): mandibuloacral dysplasia with type A lipodystrophy

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

61 retrieved; paginated sample, class counts are floors:

31 uncertain significance, 8 pathogenic, 6 conflicting classifications of pathogenicity, 6 benign, 4 likely benign, 3 benign/likely benign, 2 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4274	NM_005857.5(ZMPSTE24):c.121C>T (p.Gln41Ter)	LOC129930253	Pathogenic	criteria provided, single submitter
140532	NM_005857.5(ZMPSTE24):c.627+1G>C	ZMPSTE24	Pathogenic	criteria provided, multiple submitters, no conflicts
140536	NM_005857.5(ZMPSTE24):c.691G>T (p.Glu231Ter)	ZMPSTE24	Pathogenic	criteria provided, single submitter
140537	NM_005857.5(ZMPSTE24):c.709G>T (p.Glu237Ter)	ZMPSTE24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2441655	NM_005857.5(ZMPSTE24):c.1133_1137del (p.Gly377_Phe378insTer)	ZMPSTE24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30586	NM_005857.5(ZMPSTE24):c.1349G>A (p.Trp450Ter)	ZMPSTE24	Pathogenic	no assertion criteria provided
3382731	NM_005857.5(ZMPSTE24):c.469C>T (p.Gln157Ter)	ZMPSTE24	Pathogenic	criteria provided, single submitter
4271	NM_005857.5(ZMPSTE24):c.1085dup (p.Leu362fs)	ZMPSTE24	Pathogenic	criteria provided, multiple submitters, no conflicts
4272	NM_005857.5(ZMPSTE24):c.1018T>C (p.Trp340Arg)	ZMPSTE24	Pathogenic	no assertion criteria provided
4275	NM_005857.5(ZMPSTE24):c.743C>T (p.Pro248Leu)	ZMPSTE24	Pathogenic	criteria provided, single submitter
3382730	NM_005857.5(ZMPSTE24):c.1259_1270dup (p.Lys423_Lys424insThrPheAlaLys)	ZMPSTE24	Likely pathogenic	criteria provided, single submitter
130790	NM_005857.5(ZMPSTE24):c.325T>G (p.Cys109Gly)	ZMPSTE24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
140518	NM_005857.5(ZMPSTE24):c.1312C>T (p.Leu438Phe)	ZMPSTE24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297262	NM_005857.5(ZMPSTE24):c.770-14T>C	ZMPSTE24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297263	NM_005857.5(ZMPSTE24):c.951_954+2del	ZMPSTE24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297265	NM_005857.5(ZMPSTE24):c.1106G>A (p.Arg369Gln)	ZMPSTE24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
725823	NM_005857.5(ZMPSTE24):c.1165T>C (p.Leu389=)	ZMPSTE24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297258	NM_005857.5(ZMPSTE24):c.-13G>A	LOC129930253	Uncertain significance	criteria provided, single submitter
297259	NM_005857.5(ZMPSTE24):c.30G>T (p.Leu10Phe)	LOC129930253	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892921	NM_005857.5(ZMPSTE24):c.113C>T (p.Ala38Val)	LOC129930253	Uncertain significance	criteria provided, single submitter
875987	NM_005857.5(ZMPSTE24):c.52C>T (p.Arg18Cys)	LOC129930253	Uncertain significance	criteria provided, single submitter
1386345	NM_005857.5(ZMPSTE24):c.1416G>T (p.Met472Ile)	ZMPSTE24	Uncertain significance	criteria provided, multiple submitters, no conflicts
1514530	NM_005857.5(ZMPSTE24):c.260C>T (p.Thr87Ile)	ZMPSTE24	Uncertain significance	criteria provided, multiple submitters, no conflicts
1905058	NM_005857.5(ZMPSTE24):c.997C>A (p.Leu333Ile)	ZMPSTE24	Uncertain significance	criteria provided, multiple submitters, no conflicts
297261	NM_005857.5(ZMPSTE24):c.555A>G (p.Leu185=)	ZMPSTE24	Uncertain significance	criteria provided, single submitter
297264	NM_005857.5(ZMPSTE24):c.1050T>C (p.Ile350=)	ZMPSTE24	Uncertain significance	criteria provided, single submitter
297268	NM_005857.5(ZMPSTE24):c.*212G>T	ZMPSTE24	Uncertain significance	criteria provided, single submitter
297269	NM_005857.5(ZMPSTE24):c.*296T>C	ZMPSTE24	Uncertain significance	criteria provided, single submitter
297271	NM_005857.5(ZMPSTE24):c.*536C>T	ZMPSTE24	Uncertain significance	criteria provided, single submitter
297273	NM_005857.5(ZMPSTE24):c.*696A>G	ZMPSTE24	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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
ZMPSTE24	Strong	Autosomal recessive	mandibuloacral dysplasia with type B lipodystrophy	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZMPSTE24	Orphanet:1662	Restrictive dermopathy
ZMPSTE24	Orphanet:740	Hutchinson-Gilford progeria syndrome
ZMPSTE24	Orphanet:90154	Mandibuloacral dysplasia with type B 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
ZMPSTE24	HGNC:12877	ENSG00000084073	O75844	CAAX prenyl protease 1 homolog	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZMPSTE24	CAAX prenyl protease 1 homolog	Transmembrane metalloprotease whose catalytic activity is critical for processing lamin A/LMNA on the inner nuclear membrane and clearing clogged translocons on the endoplasmic reticulum.

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZMPSTE24	Protease	yes	3.4.24.84	Peptidase_M48, CAXX_Prtase_1, Peptidase_M48_N

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
choroid plexus epithelium	1
hair follicle	1
nephron tubule	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZMPSTE24	295	ubiquitous	marker	hair follicle, choroid plexus epithelium, nephron tubule

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ZMPSTE24	2,685

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ZMPSTE24	O75844	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
regulation of stress-activated protein kinase signaling cascade	1	16852.0×	7e-04	ZMPSTE24
regulation of mitotic cell cycle DNA replication	1	16852.0×	7e-04	ZMPSTE24
regulation of termination of RNA polymerase I transcription	1	16852.0×	7e-04	ZMPSTE24
inflammatory cell apoptotic process	1	8426.0×	7e-04	ZMPSTE24
maintenance of rDNA	1	8426.0×	7e-04	ZMPSTE24
response to DNA damage checkpoint signaling	1	8426.0×	7e-04	ZMPSTE24
prenylated protein catabolic process	1	5617.3×	7e-04	ZMPSTE24
regulation of fibroblast proliferation	1	5617.3×	7e-04	ZMPSTE24
CAAX-box protein processing	1	5617.3×	7e-04	ZMPSTE24
negative regulation of miRNA processing	1	5617.3×	7e-04	ZMPSTE24
calcium ion import into sarcoplasmic reticulum	1	5617.3×	7e-04	ZMPSTE24
regulation of hormone metabolic process	1	3370.4×	0.001	ZMPSTE24
CAMKK-AMPK signaling cascade	1	2808.7×	0.001	ZMPSTE24
cardiac ventricle development	1	2407.4×	0.001	ZMPSTE24
ventricular cardiac muscle tissue development	1	2106.5×	0.001	ZMPSTE24
growth plate cartilage development	1	2106.5×	0.001	ZMPSTE24
regulation of DNA damage response, signal transduction by p53 class mediator	1	2106.5×	0.001	ZMPSTE24
regulation of defense response to virus	1	2106.5×	0.001	ZMPSTE24
kidney morphogenesis	1	1872.4×	0.001	ZMPSTE24
cardiac conduction	1	1685.2×	0.001	ZMPSTE24
regulation of cellular senescence	1	1404.3×	0.002	ZMPSTE24
positive regulation of gene expression via chromosomal CpG island demethylation	1	1203.7×	0.002	ZMPSTE24
nuclear envelope organization	1	991.3×	0.002	ZMPSTE24
regulation of TOR signaling	1	936.2×	0.002	ZMPSTE24
regulation of ventricular cardiac muscle cell membrane repolarization	1	842.6×	0.002	ZMPSTE24
regulation of bone mineralization	1	732.7×	0.002	ZMPSTE24
regulation of multicellular organism growth	1	648.1×	0.003	ZMPSTE24
cardiac muscle cell development	1	624.1×	0.003	ZMPSTE24
cellular response to gamma radiation	1	601.9×	0.003	ZMPSTE24
regulation of glucose metabolic process	1	561.7×	0.003	ZMPSTE24

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
ZMPSTE24	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
ZMPSTE24	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ZMPSTE24	3.4.24.84	Ste24 endopeptidase

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	ZMPSTE24
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)
ZMPSTE24	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.