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Atlas / Disease / Autosomal recessive distal spinal muscular atrophy 2

Autosomal recessive distal spinal muscular atrophy 2

disease
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Also known as autosomal recessive distal spinal muscular atrophy type 2dHMNJDSMA2hereditary motor neuropathy, Jerash typeHMNJMNDJmotor neuropathy, distal, Jerash typeneuropathy, distal hereditary motor, Jerash typespinal muscular atrophy, distal, autosomal recessive, 2spinal muscular atrophy, distal, autosomal recessive, type 2

Summary

Autosomal recessive distal spinal muscular atrophy 2 (MONDO:0011585) is a disease caused by SIGMAR1 (GenCC Strong), with 4 cohort genes.

At a glance

  • Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
  • Causal gene: SIGMAR1 (GenCC Strong)
  • Cohort genes: 4
  • ClinVar variants: 184

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

TypeClassValueGeographyValidation
Cases/families30WorldwideValidated
Point prevalence<1 / 1 000 000WorldwideValidated

Identifiers

Disease identifiers

FieldValue
Canonical nameautosomal recessive distal spinal muscular atrophy 2
Mondo IDMONDO:0011585
MeSHC535715
OMIM605726
Orphanet139552
DOIDDOID:0111065
SNOMED CT763533003
UMLSC1854023
MedGen344189
GARD0010133
Is cancer (heuristic)no

Also known as: autosomal recessive distal spinal muscular atrophy type 2 · dHMNJ · DSMA2 · hereditary motor neuropathy, Jerash type · HMNJ · MNDJ · motor neuropathy, distal, Jerash type · neuropathy, distal hereditary motor, Jerash type · spinal muscular atrophy, distal, autosomal recessive, 2 · spinal muscular atrophy, distal, autosomal recessive, type 2

Data availability: 184 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › spinal cord disorder › anterior horn disorder › spinal muscular atrophy › autosomal recessive distal spinal muscular atrophy 2

Related subtypes (18): spinal muscular atrophy-progressive myoclonic epilepsy syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, spinal muscular atrophy, facioscapulohumeral type, adult-onset proximal spinal muscular atrophy, autosomal dominant, spinal muscular atrophy, segmental, spinal muscular atrophy, Ryukyuan type, scapuloperoneal spinal muscular atrophy, autosomal recessive, X-linked distal spinal muscular atrophy type 3, infantile-onset X-linked spinal muscular atrophy, autosomal recessive distal spinal muscular atrophy 1, neuronopathy, distal hereditary motor, autosomal recessive 3, neuronopathy, distal hereditary motor, autosomal recessive 4, neuronopathy, distal hereditary motor, autosomal recessive 5, neuronopathy, distal hereditary motor, autosomal dominant, bulbospinal muscular atrophy, spinal muscular atrophy with respiratory distress type 2, proximal spinal muscular atrophy, spinal muscular atrophy type 0

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

184 retrieved; paginated sample, class counts are floors:

77 likely benign, 70 uncertain significance, 16 pathogenic, 8 benign, 6 likely pathogenic, 3 conflicting classifications of pathogenicity, 2 benign/likely benign, 2 pathogenic/likely pathogenic

ClinVarVariant (HGVS)GeneClassificationReview
183041NM_006736.6(DNAJB2):c.229+1G>ADNAJB2Pathogeniccriteria provided, single submitter
217886NM_006736.6(DNAJB2):c.352+1G>ADNAJB2Pathogeniccriteria provided, multiple submitters, no conflicts
1454893NM_005866.4(SIGMAR1):c.86G>A (p.Trp29Ter)LOC130001681Pathogeniccriteria provided, single submitter
208123NM_005866.4(SIGMAR1):c.151+1G>TLOC130001681Pathogenicno assertion criteria provided
2083521NM_005866.4(SIGMAR1):c.125_126del (p.Ile42fs)LOC130001681Pathogeniccriteria provided, single submitter
569448NM_005866.4(SIGMAR1):c.13del (p.Val5fs)LOC130001681Pathogeniccriteria provided, single submitter
985499NM_005866.4(SIGMAR1):c.14_20dup (p.Arg8fs)LOC130001681Pathogeniccriteria provided, multiple submitters, no conflicts
1067324NM_005866.4(SIGMAR1):c.492G>A (p.Trp164Ter)SIGMAR1Pathogeniccriteria provided, single submitter
209190NM_005866.4(SIGMAR1):c.283dup (p.Leu95fs)SIGMAR1Pathogeniccriteria provided, multiple submitters, no conflicts
2938415NM_005866.4(SIGMAR1):c.456_471del (p.Val153fs)SIGMAR1Pathogeniccriteria provided, single submitter
2945263NM_005866.4(SIGMAR1):c.374C>A (p.Ser125Ter)SIGMAR1Pathogeniccriteria provided, single submitter
30238NM_005866.4(SIGMAR1):c.304G>C (p.Glu102Gln)SIGMAR1Pathogeniccriteria provided, multiple submitters, no conflicts
3748188NM_005866.4(SIGMAR1):c.403C>T (p.Gln135Ter)SIGMAR1Pathogeniccriteria provided, single submitter
3749597NM_005866.4(SIGMAR1):c.217_220del (p.Val73fs)SIGMAR1Pathogeniccriteria provided, single submitter
3756143NM_005866.4(SIGMAR1):c.445+1G>ASIGMAR1Pathogeniccriteria provided, single submitter
575556NM_005866.4(SIGMAR1):c.194T>A (p.Leu65Gln)SIGMAR1Pathogenic/Likely pathogeniccriteria provided, multiple submitters, no conflicts
623389NM_005866.4(SIGMAR1):c.238C>T (p.Gln80Ter)SIGMAR1Pathogeniccriteria provided, single submitter
650504NM_005866.4(SIGMAR1):c.19del (p.Arg7fs)SIGMAR1Pathogenic/Likely pathogeniccriteria provided, multiple submitters, no conflicts
183042NM_006736.6(DNAJB2):c.14A>G (p.Tyr5Cys)DNAJB2Likely pathogeniccriteria provided, single submitter
1067640NM_005866.4(SIGMAR1):c.152-2A>TSIGMAR1Likely pathogeniccriteria provided, single submitter
1285377NM_005866.4(SIGMAR1):c.109_110del (p.Phe37fs)SIGMAR1Likely pathogeniccriteria provided, single submitter
431075NM_005866.4(SIGMAR1):c.561_576del (p.Asp188fs)SIGMAR1Likely pathogeniccriteria provided, multiple submitters, no conflicts
4356097NM_005866.4(SIGMAR1):c.353-2A>GSIGMAR1Likely pathogeniccriteria provided, single submitter
873316NM_005866.4(SIGMAR1):c.448G>A (p.Glu150Lys)SIGMAR1Likely pathogeniccriteria provided, multiple submitters, no conflicts
2196903NM_005866.4(SIGMAR1):c.356G>A (p.Arg119His)SIGMAR1Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
465869NM_005866.4(SIGMAR1):c.463G>A (p.Gly155Arg)SIGMAR1Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
573115NM_005866.4(SIGMAR1):c.632G>A (p.Arg211Gln)SIGMAR1Conflicting classifications of pathogenicitycriteria provided, conflicting classifications
584345NC_000009.11:g.(?34458984)(36277059_?)dupCREB3Uncertain significancecriteria provided, single submitter
1001150NM_005866.4(SIGMAR1):c.61G>A (p.Val21Met)LOC130001681Uncertain significancecriteria provided, multiple submitters, no conflicts
1025205NM_005866.4(SIGMAR1):c.89T>C (p.Leu30Pro)LOC130001681Uncertain significancecriteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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.

GeneClassificationInheritanceDiseaseRecords
SIGMAR1StrongAutosomal recessiveautosomal recessive distal spinal muscular atrophy 26

Orphanet rare-disease linkage (cohort genes)

GeneOrphanet IDRare disease
SIGMAR1Orphanet:139552Distal hereditary motor neuropathy, Jerash type
SIGMAR1Orphanet:300605Juvenile amyotrophic lateral sclerosis
DNAJB2Orphanet:314485Young adult-onset distal hereditary motor neuropathy
DNAJB2Orphanet:443950DNAJB2-related Charcot-Marie-Tooth disease type 2

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

SubsetGenes
multi_evidence4

Cohort genes (full)

SymbolHGNCEnsemblUniProtNameEvidence
SIGMAR1HGNC:8157ENSG00000147955Q99720Sigma non-opioid intracellular receptor 1gencc,clinvar
CREB3HGNC:2347ENSG00000107175O43889Cyclic AMP-responsive element-binding protein 3clinvar
SPATA31G1HGNC:31418ENSG00000174038Q5VYM1Spermatogenesis-associated protein 31G1clinvar
DNAJB2HGNC:5228ENSG00000135924P25686DnaJ homolog subfamily B member 2clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

SymbolProtein nameFunction (lead sentence)
SIGMAR1Sigma non-opioid intracellular receptor 1Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma membrane.
CREB3Cyclic AMP-responsive element-binding protein 3Endoplasmic reticulum (ER)-bound sequence-specific transcription factor that directly binds DNA and activates transcription.
SPATA31G1Spermatogenesis-associated protein 31G1Dispensable for normal development and fertility.
DNAJB2DnaJ homolog subfamily B member 2Functions as a co-chaperone, regulating the substrate binding and activating the ATPase activity of chaperones of the HSP70/heat shock protein 70 family.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · 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.

FamilyGenesFoldFDR
Other/Unknown41.8×0.097

Per-gene assignment

SymbolFamilyDruggable?ECInterPro (top 3)
SIGMAR1Other/UnknownnoERG2_sigma1_rcpt-like
CREB3Other/UnknownnobZIP, bZIP_sf, CREB_ATF_subfamily
SPATA31G1Other/UnknownnoSpata31g1-like
DNAJB2Other/UnknownnoDnaJ_domain, UIM_dom, DnaJ_domain_CS

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)

BucketGenes
narrow (1-5 tissues)0
moderate (6-20)0
broad (>20)4
unknown0

Top tissues across cohort

TissueCohort genes
liver1
right lobe of liver1
stromal cell of endometrium1
adenohypophysis1
popliteal artery1
right testis1
cardiac muscle of right atrium1
kidney epithelium1
left ventricle myocardium1
C1 segment of cervical spinal cord1
cerebellar hemisphere1
right hemisphere of cerebellum1

Per-gene tissue summary (top 30)

SymbolBgee breadthFANTOM5 breadthSCXATop tissues
SIGMAR1282ubiquitousmarkerright lobe of liver, stromal cell of endometrium, liver
CREB3276ubiquitousmarkeradenohypophysis, popliteal artery, right testis
SPATA31G1153tissue_specificyeskidney epithelium, cardiac muscle of right atrium, left ventricle myocardium
DNAJB2281ubiquitousmarkerC1 segment of cervical spinal cord, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

SymbolInteractor count
DNAJB22,884
SIGMAR11,993
CREB31,969
SPATA31G1811

Structural data

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

Cohort genes with PDB structures (top 30)

SymbolUniProtPDB entries
SIGMAR1Q997205
DNAJB2P256861

AlphaFold-only cohort genes (top 30 by pLDDT)

SymbolUniProtpLDDT
CREB3O4388961.35
SPATA31G1Q5VYM139.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 4 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

PathwayCohort genesFoldFDRSample cohort genes
CREB3 factors activate genes1634.4×0.009CREB3
Potential therapeutics for SARS157.1×0.052SIGMAR1
SARS-CoV Infections127.7×0.072SIGMAR1
Viral Infection Pathways115.4×0.095SIGMAR1
Infectious disease112.4×0.095SIGMAR1
Disease16.5×0.147SIGMAR1

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 termCohort genesFoldFDRSample cohort genes
positive regulation of deacetylase activity15617.3×0.004CREB3
regulation of protein folding15617.3×0.004DNAJB2
negative regulation of protein deubiquitination12808.7×0.005DNAJB2
release from viral latency11872.4×0.005CREB3
negative regulation of inclusion body assembly1561.7×0.012DNAJB2
response to alcohol1510.7×0.012SIGMAR1
positive regulation of ATP-dependent activity1468.1×0.012DNAJB2
induction of positive chemotaxis1330.4×0.012CREB3
protein homotrimerization1330.4×0.012SIGMAR1
regulation of protein ubiquitination1295.6×0.012DNAJB2
negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway1280.9×0.012CREB3
positive regulation of monocyte chemotaxis1267.5×0.012CREB3
regulation of neuron apoptotic process1234.1×0.012SIGMAR1
integrated stress response signaling1234.1×0.012CREB3
negative regulation of protein binding1208.1×0.012DNAJB2
protein refolding1208.1×0.012DNAJB2
positive regulation of calcium ion transport1193.7×0.012CREB3
neuron cellular homeostasis1151.8×0.015DNAJB2
regulation of postsynapse assembly1114.6×0.019SIGMAR1
response to unfolded protein1100.3×0.019DNAJB2
endoplasmic reticulum unfolded protein response198.5×0.019CREB3
negative regulation of cell cycle196.8×0.019CREB3
lipid transport187.8×0.020SIGMAR1
DNA-templated transcription174.9×0.021CREB3
regulation of cell growth173.9×0.021CREB3
positive regulation of protein ubiquitination171.1×0.021DNAJB2
positive regulation of proteasomal ubiquitin-dependent protein catabolic process170.2×0.021DNAJB2
regulation of protein localization168.5×0.021DNAJB2
ERAD pathway160.4×0.023DNAJB2
negative regulation of cell growth148.0×0.028DNAJB2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

SymbolExample approved molecule
SIGMAR1PENTAZOCINE

Top cohort targets by molecule count

SymbolMoleculesMax phase
SIGMAR11484
CREB300
SPATA31G100
DNAJB200

Drugs targeting cohort genes (top 30)

MoleculeMax phaseTargets in cohort
PENTAZOCINE4SIGMAR1
PROGESTERONE4SIGMAR1
METHYSERGIDE4SIGMAR1
DICYCLOMINE4SIGMAR1
PROPARACAINE4SIGMAR1
PRAMOXINE4SIGMAR1
DIMENHYDRINATE4SIGMAR1
DIHYDROERGOTAMINE MESYLATE4SIGMAR1
CINACALCET HYDROCHLORIDE4SIGMAR1
AZELASTINE HYDROCHLORIDE4SIGMAR1
METHAMPHETAMINE4SIGMAR1
BENZTROPINE4SIGMAR1
LEVOBUNOLOL4SIGMAR1
DEXCHLORPHENIRAMINE4SIGMAR1
RAMELTEON4SIGMAR1
OXYBUTYNIN4SIGMAR1
MIFEPRISTONE4SIGMAR1
ILOPERIDONE4SIGMAR1
TRIHEXYPHENIDYL4SIGMAR1
TRIFLUPERIDOL4SIGMAR1
TEGASEROD MALEATE4SIGMAR1
HYDROXYCHLOROQUINE4SIGMAR1
PRAZOSIN HYDROCHLORIDE4SIGMAR1
VILAZODONE HYDROCHLORIDE4SIGMAR1
CLEMASTINE4SIGMAR1
DOXEPIN4SIGMAR1
PROPRANOLOL HYDROCHLORIDE4SIGMAR1
BETAXOLOL HYDROCHLORIDE4SIGMAR1
LOPERAMIDE HYDROCHLORIDE4SIGMAR1
TERCONAZOLE4SIGMAR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

SymbolAssaysType breakdown
SIGMAR1619Binding:610, Functional:5, ADMET:3, Unclassified:1

Cohort genes with high screening signal

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

SymbolChEMBL assays
SIGMAR1619

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 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.

CompoundMax phaseCohort target (bioactivity)
PENTAZOCINE4SIGMAR1
PROGESTERONE4SIGMAR1
METHYSERGIDE4SIGMAR1
DICYCLOMINE4SIGMAR1
PROPARACAINE4SIGMAR1
PRAMOXINE4SIGMAR1
DIMENHYDRINATE4SIGMAR1
DIHYDROERGOTAMINE MESYLATE4SIGMAR1
CINACALCET HYDROCHLORIDE4SIGMAR1
AZELASTINE HYDROCHLORIDE4SIGMAR1
METHAMPHETAMINE4SIGMAR1
BENZTROPINE4SIGMAR1
LEVOBUNOLOL4SIGMAR1
DEXCHLORPHENIRAMINE4SIGMAR1
RAMELTEON4SIGMAR1
OXYBUTYNIN4SIGMAR1
MIFEPRISTONE4SIGMAR1
ILOPERIDONE4SIGMAR1
TRIHEXYPHENIDYL4SIGMAR1
TRIFLUPERIDOL4SIGMAR1
TEGASEROD MALEATE4SIGMAR1
HYDROXYCHLOROQUINE4SIGMAR1
PRAZOSIN HYDROCHLORIDE4SIGMAR1
VILAZODONE HYDROCHLORIDE4SIGMAR1
CLEMASTINE4SIGMAR1
DOXEPIN4SIGMAR1
PROPRANOLOL HYDROCHLORIDE4SIGMAR1
BETAXOLOL HYDROCHLORIDE4SIGMAR1
LOPERAMIDE HYDROCHLORIDE4SIGMAR1
TERCONAZOLE4SIGMAR1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

TierDefinitionGenesSymbols
AApproved (phase 4 drug)1SIGMAR1
BPhased (≥1) drug, not yet approved0
CDruggable family + PDB, no drug0
DDruggable family + AlphaFold only, no drug0
EDifficult family or no structure, no drug3CREB3, SPATA31G1, DNAJB2

Undrugged target profiles

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

SymbolChEMBL assaysDrugged partners (top 3)
CREB30—
SPATA31G10—
DNAJB20—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

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Sources 70

This page pulls from 70 datasets indexed by BioBTree:

alphafoldantibodybgeebgee_evidencebindingdbbiogrid_interactionbrendabrenda_kineticscellosauruschembl_activitychembl_assaychembl_documentchembl_moleculechembl_targetcivic_evidenceclingen_dosageclinical_trialsclinvarctd_gene_interactiondepmapdiamond_similaritydoidefoensemblentrezesm2_similarityfantom5_genefantom5_promotergardgenccgenerifgogtopdbgtopdb_interactiongwasgwas_studyhgncintactinterpromedgenmeshmimmondomondochildmondoparentorphanetpatentpatent_compoundpdbpfampharmgkb_clinicalpharmgkb_genepharmgkb_guidelinepharmgkb_variantpubchempubchem_activitypubchem_assayreactomerefseqrhearnacentralsctidscxa_expressionscxa_gene_experimentsignorstring_interactiontranscriptufeatureumlsuniprot