Spinocerebellar ataxia 43

Summary

Spinocerebellar ataxia 43 (MONDO:0014867) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 25
• Phenotypes (HPO): 22

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0003477	Peripheral axonal neuropathy	Very frequent (80-99%)
HP:0008959	Distal upper limb muscle weakness	Very frequent (80-99%)
HP:0009053	Distal lower limb muscle weakness	Very frequent (80-99%)
HP:0000571	Hypometric saccades	Frequent (30-79%)
HP:0000768	Pectus carinatum	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002070	Limb ataxia	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002396	Cogwheel rigidity	Frequent (30-79%)
HP:0002936	Distal sensory impairment	Frequent (30-79%)
HP:0003387	Decreased number of large peripheral myelinated nerve fibers	Frequent (30-79%)
HP:0003693	Distal amyotrophy	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0009027	Foot dorsiflexor weakness	Frequent (30-79%)
HP:0012531	Pain	Frequent (30-79%)
HP:0002073	Progressive cerebellar ataxia	Occasional (5-29%)
HP:0006855	Cerebellar vermis atrophy	Occasional (5-29%)
HP:0000726	Dementia	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spinocerebellar ataxia 43
Mondo ID	MONDO:0014867
OMIM	617018
Orphanet	497764
DOID	DOID:0111745
UMLS	C4310763
MedGen	934730
GARD	0017917
Is cancer (heuristic)	no

Also known as: autosomal dominant cerebellar ataxia caused by mutation in MME · MME autosomal dominant cerebellar ataxia · SCA43 · spinocerebellar ataxia 43 · spinocerebellar ataxia 43; SCA43 · spinocerebellar ataxia type 43

Data availability: 25 ClinVar variants · 4 GenCC gene-disease records.

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 › autosomal dominant cerebellar ataxia › spinocerebellar ataxia 43

Related subtypes (15): GRID2-related autosomal dominant spinocerebellar ataxia, spinocerebellar ataxia 27A, spinocerebellar ataxia 9, spinocerebellar ataxia 7, autosomal dominant cerebellar ataxia type I, autosomal dominant cerebellar ataxia type III, autosomal dominant cerebellar ataxia type IV, spinocerebellar ataxia 49, spinocerebellar ataxia 48, spinocerebellar ataxia 44, spinocerebellar ataxia 47, spinocerebellar ataxia 50, spinocerebellar ataxia 27B, late-onset, spinocerebellar ataxia 51, spinocerebellar ataxia 52

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

25 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 4 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 3 pathogenic, 2 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068898	NM_007289.4(MME):c.67C>T (p.Arg23Ter)	MME	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1903584	NM_007289.4(MME):c.1730G>A (p.Gly577Asp)	MME	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
253194	NM_007289.4(MME):c.428G>A (p.Cys143Tyr)	MME	Pathogenic	no assertion criteria provided
426945	NM_007289.4(MME):c.467del (p.Pro156fs)	MME	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
432777	NM_007289.4(MME):c.1564C>T (p.Gln522Ter)	MME	Pathogenic	criteria provided, multiple submitters, no conflicts
504903	NM_007289.4(MME):c.1342C>T (p.Arg448Ter)	MME	Pathogenic	criteria provided, multiple submitters, no conflicts
930821	NM_007289.4(MME):c.594dup (p.Val199fs)	MME	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1298294	NM_007289.4(MME):c.1095-2A>C	MME	Likely pathogenic	no assertion criteria provided
3383065	NM_007289.4(MME):c.1715C>A (p.Ser572Ter)	MME	Likely pathogenic	criteria provided, single submitter
1027446	NM_007289.4(MME):c.2154G>T (p.Arg718Ser)	MME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1118432	NM_007289.4(MME):c.881A>G (p.Asn294Ser)	MME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
546951	NM_007289.4(MME):c.1946T>G (p.Ile649Ser)	MME	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1305169	NM_007289.4(MME):c.47C>A (p.Pro16Gln)	MME	Uncertain significance	criteria provided, multiple submitters, no conflicts
1424657	NM_007289.4(MME):c.1511A>T (p.Glu504Val)	MME	Uncertain significance	criteria provided, multiple submitters, no conflicts
1484264	NM_007289.4(MME):c.346G>A (p.Val116Ile)	MME	Uncertain significance	criteria provided, multiple submitters, no conflicts
1503777	NM_007289.4(MME):c.854A>G (p.Asn285Ser)	MME	Uncertain significance	criteria provided, multiple submitters, no conflicts
1509433	NM_007289.4(MME):c.139G>A (p.Ala47Thr)	MME	Uncertain significance	criteria provided, multiple submitters, no conflicts
1973628	NM_007289.4(MME):c.818T>C (p.Met273Thr)	MME	Uncertain significance	criteria provided, multiple submitters, no conflicts
3382292	NM_007289.4(MME):c.1283T>G (p.Val428Gly)	MME	Uncertain significance	criteria provided, single submitter
3588697	NM_007289.4(MME):c.187A>C (p.Ile63Leu)	MME	Uncertain significance	criteria provided, single submitter
809558	NM_007289.4(MME):c.1040A>G (p.Tyr347Cys)	MME	Uncertain significance	criteria provided, multiple submitters, no conflicts
809560	NM_007289.4(MME):c.1706A>C (p.Gln569Pro)	MME	Uncertain significance	criteria provided, multiple submitters, no conflicts
931880	NM_007289.4(MME):c.1735G>A (p.Gly579Ser)	MME	Uncertain significance	criteria provided, multiple submitters, no conflicts
707888	NM_007289.4(MME):c.2133G>A (p.Val711=)	MME	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
775918	NM_007289.4(MME):c.1255A>C (p.Met419Leu)	MME	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 4 · 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
MME	Supportive	Autosomal dominant	spinocerebellar ataxia 43	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MME	Orphanet:495274	Charcot-Marie-Tooth disease type 2T
MME	Orphanet:497757	MME-related autosomal dominant Charcot Marie Tooth disease type 2
MME	Orphanet:497764	Spinocerebellar ataxia type 43
MME	Orphanet:69063	Congenital membranous nephropathy due to fetomaternal anti-neutral endopeptidase alloimmunization

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
MME	HGNC:7154	ENSG00000196549	P08473	Neprilysin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MME	Neprilysin	Thermolysin-like specificity, but is almost confined on acting on polypeptides of up to 30 amino acids.

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)
MME	Protease	yes	3.4.24.11	Peptidase_M13, Peptidase_M13_N, Peptidase_M13_C

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
jejunal mucosa	1
metanephric glomerulus	1
renal glomerulus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MME	212	ubiquitous	marker	jejunal mucosa, renal glomerulus, metanephric glomerulus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MME	2,648

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MME	P08473	16

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Physiological factors	1	671.8×	0.006	MME
Metabolism of Angiotensinogen to Angiotensins	1	634.4×	0.006	MME
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	543.8×	0.006	MME
Peptide hormone metabolism	1	271.9×	0.009	MME
Cardiac conduction	1	108.8×	0.018	MME
Muscle contraction	1	77.2×	0.022	MME
Innate Immune System	1	25.5×	0.054	MME
Neutrophil degranulation	1	23.1×	0.054	MME
Immune System	1	13.0×	0.081	MME
Metabolism of proteins	1	12.4×	0.081	MME

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
neuropeptide processing	1	16852.0×	0.002	MME
creatinine metabolic process	1	8426.0×	0.002	MME
substance P catabolic process	1	5617.3×	0.002	MME
amygdala development	1	2808.7×	0.002	MME
hormone catabolic process	1	2808.7×	0.002	MME
bradykinin catabolic process	1	2407.4×	0.002	MME
amyloid-beta clearance by cellular catabolic process	1	2106.5×	0.002	MME
amyloid-beta metabolic process	1	1532.0×	0.002	MME
cellular response to UV-A	1	1404.3×	0.002	MME
cellular response to UV-B	1	1404.3×	0.002	MME
angiotensin maturation	1	1296.3×	0.002	MME
peptide metabolic process	1	1203.7×	0.002	MME
replicative senescence	1	991.3×	0.002	MME
amyloid-beta clearance	1	936.2×	0.002	MME
positive regulation of long-term synaptic potentiation	1	674.1×	0.003	MME
positive regulation of neurogenesis	1	581.1×	0.003	MME
cellular response to cytokine stimulus	1	543.6×	0.003	MME
placenta development	1	443.5×	0.004	MME
sensory perception of pain	1	374.5×	0.004	MME
response to estrogen	1	343.9×	0.004	MME
learning or memory	1	240.7×	0.005	MME
protein catabolic process	1	237.3×	0.005	MME
hippocampus development	1	230.8×	0.005	MME
lung development	1	198.3×	0.006	MME
memory	1	183.2×	0.006	MME
protein processing	1	170.2×	0.007	MME
kidney development	1	140.4×	0.008	MME
multicellular organism growth	1	137.0×	0.008	MME
proteolysis	1	34.2×	0.029	MME

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MME	4	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CYCLOVALONE	2	MME
OMAPATRILAT	2	MME
SAMPATRILAT	2	MME
CANDOXATRILAT	2	MME

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MME	125	Binding:110, ADMET:15

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MME	3.4.24.11	neprilysin

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MME	125

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

4 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)
CYCLOVALONE	2	MME
OMAPATRILAT	2	MME
SAMPATRILAT	2	MME
CANDOXATRILAT	2	MME

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	1	MME
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.