Juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome

Summary

Juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome (MONDO:0014523) is a disease caused by DNAJC3 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DNAJC3 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 13
• Phenotypes (HPO): 15

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0000819	Diabetes mellitus	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002522	Areflexia of lower limbs	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0004325	Decreased body weight	Frequent (30-79%)
HP:0006827	Atrophy of the spinal cord	Frequent (30-79%)
HP:0007108	Demyelinating peripheral neuropathy	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0007366	Atrophy/Degeneration affecting the brainstem	Frequent (30-79%)
HP:0008619	Bilateral sensorineural hearing impairment	Frequent (30-79%)
HP:0010871	Sensory ataxia	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0003487	Babinski sign	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome
Mondo ID	MONDO:0014523
OMIM	616192
Orphanet	445062
UMLS	C4015436
MedGen	863873
GARD	0017768
Is cancer (heuristic)	no

Also known as: ACPHD · ataxia, combined cerebellar and peripheral, with hearing loss and diabetes mellitus · combined cerebellar and peripheral ataxia-hearing loss-diabetes mellitus syndrome

Data availability: 13 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › atactic disorder › hereditary ataxia › juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome

Related subtypes (19): ataxia with fasciculations, muscular atrophy-ataxia-retinitis pigmentosa-diabetes mellitus syndrome, myoclonus-cerebellar ataxia-deafness syndrome, cataract-ataxia-deafness syndrome, ataxia-hypogonadism-choroidal dystrophy syndrome, ichthyosis-hepatosplenomegaly-cerebellar degeneration syndrome, Richards-Rundle syndrome, spinocerebellar ataxia-dysmorphism syndrome, ataxia-tapetoretinal degeneration syndrome, hereditary spastic paraplegia 7, autosomal dominant sensory ataxia 1, EAST syndrome, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, hereditary episodic ataxia, spastic ataxia, tremor-ataxia-central hypomyelination syndrome, hereditary cerebellar ataxia, autosomal recessive ataxia due to PEX16 deficiency, autosomal recessive ataxia due to PEX2 deficiency

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

13 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
1693484	NM_006260.5(DNAJC3):c.393+2T>G	DNAJC3	Pathogenic	no assertion criteria provided
1693485	NM_006260.5(DNAJC3):c.393+2T>C	DNAJC3	Pathogenic	no assertion criteria provided
1693487	NM_006260.5(DNAJC3):c.1A>G (p.Met1Val)	DNAJC3	Pathogenic	no assertion criteria provided
1693488	NM_006260.5(DNAJC3):c.1036C>T (p.Arg346Ter)	DNAJC3	Pathogenic	no assertion criteria provided
3768963	NM_006260.5(DNAJC3):c.435dup (p.Ser146fs)	DNAJC3	Pathogenic	criteria provided, single submitter
429787	NM_006260.5(DNAJC3):c.1177C>T (p.Arg393Ter)	DNAJC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88854	NM_001256864.2(DNAJC6):c.801-2A>G	DNAJC6	Pathogenic	no assertion criteria provided
1693486	NM_006260.5(DNAJC3):c.1367_1370del (p.Lys456fs)	DNAJC3	Likely pathogenic	criteria provided, single submitter
1803129	NM_006260.5(DNAJC3):c.1305del (p.Glu436fs)	DNAJC3	Likely pathogenic	criteria provided, single submitter
162620	NM_006260.5(DNAJC3):c.580C>T (p.Arg194Ter)	DNAJC3	Conflicting classifications of pathogenicity	no assertion criteria provided
988565	NM_006260.5(DNAJC3):c.1243C>T (p.Arg415Ter)	DNAJC3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3236345	NM_006260.5(DNAJC3):c.729-1G>A	DNAJC3	Uncertain significance	criteria provided, single submitter
1803288	NM_201589.4(MAFA):c.767A>C (p.Lys256Thr)	MAFA	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
DNAJC3	Strong	Autosomal recessive	juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNAJC3	Orphanet:445062	Juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome
DNAJC6	Orphanet:2828	Young-onset Parkinson disease
DNAJC6	Orphanet:391411	Atypical juvenile parkinsonism

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DNAJC3	HGNC:9439	ENSG00000102580	Q13217	DnaJ homolog subfamily C member 3	gencc,clinvar
DNAJC6	HGNC:15469	ENSG00000116675	O75061	Auxilin	clinvar
MAFA	HGNC:23145	ENSG00000182759	Q8NHW3	Transcription factor MafA	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNAJC3	DnaJ homolog subfamily C member 3	Involved in the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress.
DNAJC6	Auxilin	May act as a protein phosphatase and/or a lipid phosphatase.
MAFA	Transcription factor MafA	Transcription factor that activates insulin gene expression.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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
Complement	1	89.3×	0.033
Phosphatase	1	28.0×	0.053
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNAJC3	Complement	yes		DnaJ_domain, TPR-like_helical_dom_sf, TPR_rpt
DNAJC6	Phosphatase	yes		Tyr_Pase_dom, DnaJ_domain, Tensin_C2-dom
MAFA	Transcription factor	no		bZIP_Maf, bZIP, TF_DNA-bd_sf

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
caput epididymis	1
corpus epididymis	1
oocyte	1
Brodmann (1909) area 23	1
endothelial cell	1
substantia nigra pars compacta	1
gastrocnemius	1
hindlimb stylopod muscle	1
quadriceps femoris	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNAJC3	270	ubiquitous	marker	corpus epididymis, caput epididymis, oocyte
DNAJC6	227	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, substantia nigra pars compacta
MAFA	89	broad	marker	quadriceps femoris, hindlimb stylopod muscle, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNAJC6	3,784
DNAJC3	2,961
MAFA	478

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNAJC3	Q13217	2
MAFA	Q8NHW3	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAJC6	O75061	64.29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of beta-cell development	1	237.9×	0.034	MAFA
Regulation of gene expression in beta cells	1	173.0×	0.034	MAFA
Lysosome Vesicle Biogenesis	1	108.8×	0.034	DNAJC6
trans-Golgi Network Vesicle Budding	1	84.6×	0.034	DNAJC6
XBP1(S) activates chaperone genes	1	71.8×	0.034	DNAJC3
Maturation of DENV proteins	1	70.5×	0.034	DNAJC3
Golgi Associated Vesicle Biogenesis	1	66.8×	0.034	DNAJC6
PKR-mediated signaling	1	47.0×	0.042	DNAJC3
Viral mRNA Translation	1	42.3×	0.042	DNAJC3
Post-translational protein phosphorylation	1	33.4×	0.046	DNAJC3
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	28.8×	0.046	DNAJC3
Clathrin-mediated endocytosis	1	28.4×	0.046	DNAJC6
Membrane Trafficking	1	12.4×	0.096	DNAJC6
Vesicle-mediated transport	1	11.6×	0.096	DNAJC6
Neutrophil degranulation	1	7.7×	0.133	DNAJC3
Developmental Biology	1	4.8×	0.194	MAFA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of translation initiation in response to endoplasmic reticulum stress	1	5617.3×	0.002	DNAJC3
negative regulation of endoplasmic reticulum stress-induced eIF2 alpha phosphorylation	1	5617.3×	0.002	DNAJC3
regulation of clathrin coat assembly	1	2808.7×	0.002	DNAJC6
synaptic vesicle uncoating	1	1872.4×	0.002	DNAJC6
negative regulation of translation in response to endoplasmic reticulum stress	1	1872.4×	0.002	DNAJC3
clathrin coat disassembly	1	1404.3×	0.002	DNAJC6
regulation of clathrin-dependent endocytosis	1	561.7×	0.005	DNAJC6
intracellular transport	1	510.7×	0.005	DNAJC6
protein folding in endoplasmic reticulum	1	468.1×	0.005	DNAJC3
synaptic vesicle recycling	1	401.2×	0.005	DNAJC6
cellular response to cold	1	351.1×	0.005	DNAJC3
clathrin-dependent endocytosis	1	193.7×	0.009	DNAJC6
obsolete proteolysis involved in protein catabolic process	1	175.5×	0.009	DNAJC3
insulin secretion	1	144.0×	0.010	MAFA
response to unfolded protein	1	100.3×	0.014	DNAJC3
response to glucose	1	85.1×	0.015	MAFA
defense response to virus	1	23.1×	0.053	DNAJC3
negative regulation of apoptotic process	1	11.6×	0.098	DNAJC3
regulation of DNA-templated transcription	1	10.5×	0.102	MAFA
positive regulation of transcription by RNA polymerase II	1	5.0×	0.198	MAFA
regulation of transcription by RNA polymerase II	1	3.9×	0.236	MAFA

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
DNAJC3	0	0
DNAJC6	0	0
MAFA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	DNAJC3
D	Druggable family + AlphaFold only, no drug	1	DNAJC6
E	Difficult family or no structure, no drug	1	MAFA

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DNAJC3	0	—
DNAJC6	0	—
MAFA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.