Multicentric carpo-tarsal osteolysis with or without nephropathy

Summary

Multicentric carpo-tarsal osteolysis with or without nephropathy (MONDO:0008152) is a disease caused by MAFB (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: MAFB (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 104
• Phenotypes (HPO): 21

Clinical features

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0000093	Proteinuria	Very frequent (80-99%)
HP:0000325	Triangular face	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000520	Proptosis	Very frequent (80-99%)
HP:0001225	Wrist swelling	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001376	Limitation of joint mobility	Very frequent (80-99%)
HP:0001495	Carpal osteolysis	Very frequent (80-99%)
HP:0001504	Metacarpal osteolysis	Very frequent (80-99%)
HP:0002797	Osteolysis	Very frequent (80-99%)
HP:0003019	Abnormality of the wrist	Very frequent (80-99%)
HP:0003100	Slender long bone	Very frequent (80-99%)
HP:0003457	EMG abnormality	Very frequent (80-99%)
HP:0004326	Cachexia	Very frequent (80-99%)
HP:0000112	Nephropathy	Frequent (30-79%)
HP:0100490	Camptodactyly of finger	Frequent (30-79%)
HP:0000431	Wide nasal bridge	Occasional (5-29%)
HP:0000506	Telecanthus	Occasional (5-29%)
HP:0001561	Polyhydramnios	Occasional (5-29%)
HP:0002714	Downturned corners of mouth	Occasional (5-29%)
HP:0005930	Abnormality of epiphysis morphology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	multicentric carpo-tarsal osteolysis with or without nephropathy
Mondo ID	MONDO:0008152
MeSH	C567171
OMIM	166300
Orphanet	2774
DOID	DOID:0111534
SNOMED CT	766992008
UMLS	C2674705
MedGen	436237
GARD	0003818
Is cancer (heuristic)	no

Also known as: Carnevale canun Mendoza syndrome · idiopathic multicentric osteolysis with or without nephropathy · MCTO · multicentric carpo-tarsal osteolysis with or without nephropathy · multicentric carpotarsal osteolysis syndrome · multicentric osteolysis nephropathy

Data availability: 104 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › primary osteolysis › multicentric carpo-tarsal osteolysis with or without nephropathy

Related subtypes (13): acroosteolysis, pacman dysplasia, familial expansile osteolysis, Hutchinson-Gilford progeria syndrome, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, hyaline fibromatosis syndrome, autosomal recessive distal osteolysis syndrome, Paget disease of bone 2, early-onset, talo-patello-scaphoid osteolysis, Nestor-Guillermo progeria syndrome, mandibuloacral dysplasia, phalangeal microgeodic syndrome, multicentric osteolysis-nodulosis-arthropathy spectrum

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

104 retrieved; paginated sample, class counts are floors:

71 uncertain significance, 10 benign, 7 conflicting classifications of pathogenicity, 7 pathogenic, 4 likely pathogenic, 2 benign/likely benign, 2 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
30768	NM_005461.5(MAFB):c.184A>C (p.Thr62Pro)	MAFB	Pathogenic	no assertion criteria provided
30769	NM_005461.5(MAFB):c.208T>G (p.Ser70Ala)	MAFB	Pathogenic	no assertion criteria provided
30770	NM_005461.5(MAFB):c.209C>T (p.Ser70Leu)	MAFB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30771	NM_005461.5(MAFB):c.211C>T (p.Pro71Ser)	MAFB	Pathogenic	no assertion criteria provided
30772	NM_005461.5(MAFB):c.212C>T (p.Pro71Leu)	MAFB	Pathogenic	criteria provided, single submitter
30773	NM_005461.5(MAFB):c.161C>T (p.Ser54Leu)	MAFB	Pathogenic	criteria provided, multiple submitters, no conflicts
3381372	NM_005461.5(MAFB):c.176C>T (p.Pro59Leu)	MAFB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
803608	NM_005461.5(MAFB):c.185C>T (p.Thr62Ile)	MAFB	Pathogenic	criteria provided, single submitter
807627	NM_005461.5(MAFB):c.184A>G (p.Thr62Ala)	MAFB	Pathogenic	criteria provided, multiple submitters, no conflicts
2501713	NM_005461.5(MAFB):c.203C>T (p.Pro68Leu)	MAFB	Likely pathogenic	criteria provided, single submitter
3235198	NM_005461.5(MAFB):c.176C>G (p.Pro59Arg)	MAFB	Likely pathogenic	criteria provided, single submitter
684763	NM_005461.5(MAFB):c.173C>G (p.Thr58Arg)	MAFB	Likely pathogenic	criteria provided, single submitter
813951	NM_005461.5(MAFB):c.197C>T (p.Ser66Phe)	MAFB	Likely pathogenic	criteria provided, single submitter
1590748	NM_005461.5(MAFB):c.294G>C (p.Glu98Asp)	MAFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2080784	NM_005461.5(MAFB):c.886G>A (p.Val296Ile)	MAFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2909734	NM_005461.5(MAFB):c.340T>C (p.Ser114Pro)	MAFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338412	NM_005461.5(MAFB):c.189G>A (p.Pro63=)	MAFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895055	NM_005461.5(MAFB):c.648C>T (p.Leu216=)	MAFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895057	NM_005461.5(MAFB):c.393C>A (p.His131Gln)	MAFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895058	NM_005461.5(MAFB):c.368G>C (p.Ser123Thr)	MAFB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
899235	NM_005461.5(MAFB):c.-269G>C	LOC130065872	Uncertain significance	criteria provided, single submitter
899236	NM_005461.5(MAFB):c.-297G>T	LOC130065872	Uncertain significance	criteria provided, single submitter
1480401	NM_005461.5(MAFB):c.457G>C (p.Asp153His)	MAFB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1512800	NM_005461.5(MAFB):c.577C>T (p.His193Tyr)	MAFB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1525186	NM_005461.5(MAFB):c.617G>A (p.Ser206Asn)	MAFB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1940963	NM_005461.5(MAFB):c.227C>A (p.Thr76Asn)	MAFB	Uncertain significance	criteria provided, multiple submitters, no conflicts
2549852	NM_005461.5(MAFB):c.863C>T (p.Ala288Val)	MAFB	Uncertain significance	criteria provided, multiple submitters, no conflicts
2988873	NM_005461.5(MAFB):c.405T>A (p.His135Gln)	MAFB	Uncertain significance	criteria provided, multiple submitters, no conflicts
338374	NM_005461.5(MAFB):c.*1803C>T	MAFB	Uncertain significance	criteria provided, single submitter
338375	NM_005461.5(MAFB):c.*1787T>C	MAFB	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
MAFB	Definitive	Autosomal dominant	multicentric carpo-tarsal osteolysis with or without nephropathy	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAFB	Orphanet:233	Duane retraction syndrome
MAFB	Orphanet:2774	Multicentric carpo-tarsal osteolysis with or without nephropathy
MAFB	Orphanet:529574	Duane retraction syndrome with congenital deafness

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
MAFB	HGNC:6408	ENSG00000204103	Q9Y5Q3	Transcription factor MafB	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAFB	Transcription factor MafB	Acts as a transcriptional activator or repressor.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MAFB	Transcription factor	no		bZIP_Maf, bZIP, TF_DNA-bd_sf

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
gingiva	1
renal glomerulus	1
skin of hip	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAFB	277	ubiquitous	marker	renal glomerulus, skin of hip, gingiva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAFB	2,671

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MAFB	Q9Y5Q3	63.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Activation of HOX genes during differentiation	1	439.2×	0.007	MAFB
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	91.4×	0.016	MAFB
Developmental Biology	1	14.5×	0.069	MAFB

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
rhombomere 6 development	1	16852.0×	9e-04	MAFB
rhombomere 5 development	1	8426.0×	9e-04	MAFB
abducens nerve formation	1	8426.0×	9e-04	MAFB
brain segmentation	1	5617.3×	0.001	MAFB
regulation of myeloid cell differentiation	1	3370.4×	0.001	MAFB
cornified envelope assembly	1	2808.7×	0.001	MAFB
segment specification	1	2106.5×	0.002	MAFB
negative regulation of erythrocyte differentiation	1	1532.0×	0.002	MAFB
integrated stress response signaling	1	702.2×	0.003	MAFB
sensory organ development	1	674.1×	0.003	MAFB
respiratory gaseous exchange by respiratory system	1	624.1×	0.003	MAFB
negative regulation of osteoclast differentiation	1	543.6×	0.004	MAFB
T cell differentiation in thymus	1	411.0×	0.004	MAFB
thymus development	1	337.0×	0.005	MAFB
inner ear morphogenesis	1	300.9×	0.005	MAFB
response to nutrient	1	295.6×	0.005	MAFB
keratinocyte differentiation	1	247.8×	0.006	MAFB
fat cell differentiation	1	181.2×	0.007	MAFB
protein processing	1	170.2×	0.007	MAFB
in utero embryonic development	1	72.0×	0.017	MAFB
regulation of DNA-templated transcription	1	31.6×	0.036	MAFB
positive regulation of DNA-templated transcription	1	27.9×	0.039	MAFB
negative regulation of transcription by RNA polymerase II	1	17.7×	0.059	MAFB
regulation of transcription by RNA polymerase II	1	11.7×	0.086	MAFB

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAFB	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MAFB

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)
MAFB	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.