Neuronopathy, distal hereditary motor, autosomal dominant 1

Summary

Neuronopathy, distal hereditary motor, autosomal dominant 1 (MONDO:0008451) is a disease with 2 cohort genes and 1 clinical trial.

At a glance

• Cohort genes: 2
• ClinVar variants: 2
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronopathy, distal hereditary motor, autosomal dominant 1
Mondo ID	MONDO:0008451
MeSH	C566675
OMIM	182960
Orphanet	139518
DOID	DOID:0111200
NCIT	C132826
UMLS	C1866784
MedGen	356618
GARD	0016953
Is cancer (heuristic)	no

Also known as: autosomal dominant distal juvenile spinal muscular atrophy type 1 · Charcot-Marie-Tooth disease, spinal, I · DHMN1 · dHMN1 · distal hereditary motor neuronopathy type I · HMN1 · neuronopathy, distal hereditary motor, type 1 · neuronopathy, distal hereditary motor, type I

Data availability: 2 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › neuronopathy, distal hereditary motor, autosomal dominant › neuronopathy, distal hereditary motor, autosomal dominant 1

Related subtypes (10): hereditary spastic paraplegia 17, neuronopathy, distal hereditary motor, autosomal dominant 8, distal hereditary motor neuropathy type 2, distal hereditary motor neuropathy type 7, neuronopathy, distal hereditary motor, type 9, neuronopathy, distal hereditary motor, type 5, neuronopathy, distal hereditary motor, autosomal dominant 10, neuronopathy, distal hereditary motor, autosomal dominant 11, myopathy, myofibrillar, 13, with rimmed vacuoles, neuronopathy, distal hereditary motor, autosomal dominant 15

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

2 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
582766	NM_002180.3(IGHMBP2):c.1313dup (p.Thr439fs)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1969000	NM_000052.7(ATP7A):c.332A>C (p.Lys111Thr)	ATP7A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IGHMBP2	Orphanet:443073	Charcot-Marie-Tooth disease type 2S
IGHMBP2	Orphanet:98920	Spinal muscular atrophy with respiratory distress type 1
ATP7A	Orphanet:139557	X-linked distal spinal muscular atrophy type 3
ATP7A	Orphanet:198	Occipital horn syndrome
ATP7A	Orphanet:388	Hirschsprung disease
ATP7A	Orphanet:565	Menkes disease

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IGHMBP2	HGNC:5542	ENSG00000132740	P38935	DNA-binding protein SMUBP-2	clinvar
ATP7A	HGNC:869	ENSG00000165240	Q04656	Copper-transporting ATPase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IGHMBP2	DNA-binding protein SMUBP-2	5’ to 3’ helicase that unwinds RNA and DNA duplexes in an ATP-dependent reaction.
ATP7A	Copper-transporting ATPase 1	ATP-driven copper (Cu(+)) ion pump that plays an important role in intracellular copper ion homeostasis.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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	2	8.3×	0.015

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IGHMBP2	Transcription factor	no	3.6.4.12	Znf_AN1, R3H_dom, AAA+_ATPase
ATP7A	Transcription factor	no	7.2.2.8	P_typ_ATPase, HMA_dom, HMA_Cu_ion-bd

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
esophagogastric junction muscularis propria	1
lower esophagus muscularis layer	1
mucosa of stomach	1
buccal mucosa cell	1
trabecular bone tissue	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IGHMBP2	189	ubiquitous	yes	mucosa of stomach, esophagogastric junction muscularis propria, lower esophagus muscularis layer
ATP7A	275	ubiquitous	marker	buccal mucosa cell, trabecular bone tissue, upper leg skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP7A	3,901
IGHMBP2	1,265

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP7A	Q04656	22
IGHMBP2	P38935	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 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
Ion influx/efflux at host-pathogen interface	1	2855.0×	0.004	ATP7A
Detoxification of Reactive Oxygen Species	1	300.5×	0.013	ATP7A
Antimicrobial peptides	1	223.9×	0.013	ATP7A
Ion transport by P-type ATPases	1	207.6×	0.013	ATP7A
Cellular response to chemical stress	1	142.8×	0.015	ATP7A
Ion channel transport	1	96.0×	0.019	ATP7A
Cellular responses to stress	1	36.8×	0.043	ATP7A
Cellular responses to stimuli	1	31.5×	0.044	ATP7A
Innate Immune System	1	25.5×	0.044	ATP7A
Transport of small molecules	1	25.1×	0.044	ATP7A
Immune System	1	13.0×	0.077	ATP7A

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
obsolete negative regulation of catecholamine metabolic process	1	8426.0×	0.002	ATP7A
obsolete L-tryptophan metabolic process	1	5617.3×	0.002	ATP7A
epinephrine metabolic process	1	5617.3×	0.002	ATP7A
copper ion export	1	5617.3×	0.002	ATP7A
obsolete tyrosine metabolic process	1	4213.0×	0.002	ATP7A
catecholamine metabolic process	1	4213.0×	0.002	ATP7A
T-helper cell differentiation	1	3370.4×	0.002	ATP7A
copper ion import	1	2407.4×	0.002	ATP7A
pyramidal neuron development	1	2106.5×	0.002	ATP7A
norepinephrine biosynthetic process	1	2106.5×	0.002	ATP7A
copper ion transport	1	1685.2×	0.002	ATP7A
serotonin metabolic process	1	1685.2×	0.002	ATP7A
norepinephrine metabolic process	1	1532.0×	0.002	ATP7A
elastic fiber assembly	1	1532.0×	0.002	ATP7A
positive regulation of melanin biosynthetic process	1	1404.3×	0.002	ATP7A
regulation of oxidative phosphorylation	1	1203.7×	0.002	ATP7A
detoxification of copper ion	1	1123.5×	0.002	ATP7A
removal of superoxide radicals	1	1053.2×	0.002	ATP7A
cerebellar Purkinje cell differentiation	1	1053.2×	0.002	ATP7A
dopamine metabolic process	1	991.3×	0.002	ATP7A
intracellular copper ion homeostasis	1	936.2×	0.002	ATP7A
central nervous system neuron development	1	802.5×	0.002	ATP7A
release of cytochrome c from mitochondria	1	702.2×	0.003	ATP7A
pigmentation	1	702.2×	0.003	ATP7A
hair follicle morphogenesis	1	495.6×	0.003	ATP7A
ATP metabolic process	1	468.1×	0.003	ATP7A
neuron cellular homeostasis	1	455.5×	0.003	ATP7A
skin development	1	443.5×	0.003	ATP7A
dendrite morphogenesis	1	432.1×	0.003	ATP7A
blood vessel remodeling	1	383.0×	0.004	ATP7A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IGHMBP2	0	0
ATP7A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ATP7A	11	Binding:11

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
IGHMBP2	3.6.4.12	DNA helicase
ATP7A	7.2.2.8, 7.2.2.9	P-type Cu+ transporter, P-type Cu2+ transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	IGHMBP2, ATP7A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
IGHMBP2	0	—
ATP7A	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04193228	Not specified	COMPLETED	Muscle Structure, Function and Gait in dHMN