hereditary motor and sensory neuropathy, Okinawa type

Summary

hereditary motor and sensory neuropathy, Okinawa type (MONDO:0011468) is a disease caused by TFG (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: TFG (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 380
• Phenotypes (HPO): 28

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		120	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0001284	Areflexia	Very frequent (80-99%)
HP:0003474	Somatic sensory dysfunction	Very frequent (80-99%)
HP:0003484	Upper limb muscle weakness	Very frequent (80-99%)
HP:0007340	Lower limb muscle weakness	Very frequent (80-99%)
HP:0011964	Intermittent painful muscle spasms	Very frequent (80-99%)
HP:0012735	Cough	Very frequent (80-99%)
HP:0030179	Abnormal peripheral action potential amplitude	Very frequent (80-99%)
HP:0030200	Fatiguable weakness of proximal limb muscles	Very frequent (80-99%)
HP:0000079	Abnormality of the urinary system	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0002483	Bulbar signs	Frequent (30-79%)
HP:0002540	Inability to walk	Frequent (30-79%)
HP:0002936	Distal sensory impairment	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0003698	Difficulty standing	Frequent (30-79%)
HP:0007289	Limb fasciculations	Frequent (30-79%)
HP:0010546	Muscle fibrillation	Frequent (30-79%)
HP:0030007	EMG: positive sharp waves	Frequent (30-79%)
HP:0031910	Abnormal cranial nerve physiology	Frequent (30-79%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002094	Dyspnea	Occasional (5-29%)
HP:0002878	Respiratory failure	Occasional (5-29%)
HP:0004887	Respiratory failure requiring assisted ventilation	Occasional (5-29%)
HP:0010827	Abnormality of the seventh cranial nerve	Occasional (5-29%)
HP:0011014	Abnormal glucose homeostasis	Occasional (5-29%)
HP:0011470	Nasogastric tube feeding in infancy	Occasional (5-29%)
HP:0011951	Aspiration pneumonia	Occasional (5-29%)
HP:0410262	Lower cranial nerve dysfunction	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary motor and sensory neuropathy, Okinawa type
Mondo ID	MONDO:0011468
MeSH	C535717
OMIM	604484
Orphanet	90117
UMLS	C1858338
MedGen	346886
GARD	0010131
Is cancer (heuristic)	no

Also known as: hereditary motor and sensory neuropathy, proximal type · HMSNO · HMSNP · neuropathy, hereditary motor and sensory, Okinawa type

Data availability: 380 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › motor peripheral neuropathy › hereditary motor and sensory neuropathy, Okinawa type

Related subtypes (8): motor nerve neuritis, glossopharyngeal motor neuropathy, Charcot-Marie-Tooth disease type 5, neuropathy, hereditary motor and sensory, type 6A, Charcot-Marie-Tooth disease type 4G, Charcot-Marie-Tooth disease axonal type 2C, neuropathy, hereditary motor and sensory, type 6B, peripheral motor neuropathy, childhood-onset, biotin-responsive

Subtypes (1): autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutation

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

380 retrieved; paginated sample, class counts are floors:

196 uncertain significance, 154 likely benign, 11 benign, 10 conflicting classifications of pathogenicity, 5 benign/likely benign, 2 pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
100909	NM_006070.6(TFG):c.316C>T (p.Arg106Cys)	TFG	Pathogenic	criteria provided, multiple submitters, no conflicts
1452866	NM_006070.6(TFG):c.64C>T (p.Arg22Trp)	TFG	Pathogenic	criteria provided, multiple submitters, no conflicts
156445	NM_006070.6(TFG):c.806G>T (p.Gly269Val)	TFG	Pathogenic/Likely pathogenic	no assertion criteria provided
37089	NM_006070.6(TFG):c.854C>T (p.Pro285Leu)	TFG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1039628	NM_006070.6(TFG):c.738G>C (p.Gln246His)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1075540	NM_006070.6(TFG):c.317G>A (p.Arg106His)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1907305	NM_006070.6(TFG):c.968A>G (p.Asn323Ser)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1986386	NM_006070.6(TFG):c.325C>T (p.Leu109=)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245772	NM_006070.6(TFG):c.1060C>G (p.Pro354Ala)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
466412	NM_006070.6(TFG):c.988A>G (p.Thr330Ala)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
581201	NM_006070.6(TFG):c.1199G>A (p.Arg400Gln)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
582975	NM_006070.6(TFG):c.310T>C (p.Tyr104His)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
706581	NM_006070.6(TFG):c.1048G>A (p.Ala350Thr)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
779515	NM_006070.6(TFG):c.771G>A (p.Gln257=)	TFG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003573	NM_006070.6(TFG):c.373C>T (p.Pro125Ser)	TFG	Uncertain significance	criteria provided, single submitter
1004051	NM_006070.6(TFG):c.198A>G (p.Ile66Met)	TFG	Uncertain significance	criteria provided, single submitter
1009525	NM_006070.6(TFG):c.9_10delinsGA (p.Gln4Lys)	TFG	Uncertain significance	criteria provided, single submitter
1011451	NM_006070.6(TFG):c.353G>A (p.Arg118His)	TFG	Uncertain significance	criteria provided, single submitter
1019608	NM_006070.6(TFG):c.986dup (p.Tyr329Ter)	TFG	Uncertain significance	criteria provided, single submitter
1019766	NM_006070.6(TFG):c.820+3G>A	TFG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1025286	NM_006070.6(TFG):c.850C>G (p.Gln284Glu)	TFG	Uncertain significance	criteria provided, single submitter
1030071	NM_006070.6(TFG):c.320G>C (p.Arg107Pro)	TFG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1035040	NM_006070.6(TFG):c.61A>T (p.Ile21Phe)	TFG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1051770	NM_006070.6(TFG):c.1163T>G (p.Phe388Cys)	TFG	Uncertain significance	criteria provided, single submitter
1052695	NM_006070.6(TFG):c.622G>A (p.Asp208Asn)	TFG	Uncertain significance	criteria provided, single submitter
1054786	NM_006070.6(TFG):c.34A>G (p.Ile12Val)	TFG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1062624	NC_000003.11:g.(?100455410)(100463785_?)del	TFG	Uncertain significance	criteria provided, single submitter
1063471	NM_006070.6(TFG):c.499G>A (p.Ala167Thr)	TFG	Uncertain significance	criteria provided, single submitter
1313772	NM_006070.6(TFG):c.1147C>T (p.Arg383Cys)	TFG	Uncertain significance	criteria provided, multiple submitters, no conflicts
1358338	NM_006070.6(TFG):c.293A>C (p.Glu98Ala)	TFG	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 5 · 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
TFG	Strong	Autosomal dominant	hereditary motor and sensory neuropathy, Okinawa type	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TFG	Orphanet:146	Differentiated thyroid carcinoma
TFG	Orphanet:209916	Extraskeletal myxoid chondrosarcoma
TFG	Orphanet:431329	Autosomal recessive spastic paraplegia type 57
TFG	Orphanet:435819	Autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutation
TFG	Orphanet:90117	Hereditary motor and sensory neuropathy, Okinawa type

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
TFG	HGNC:11758	ENSG00000114354	Q92734	Protein TFG	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TFG	Protein TFG	Plays a role in the normal dynamic function of the endoplasmic reticulum (ER) and its associated microtubules.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TFG	Other/Unknown	no		PB1_dom, TFG, PB1_TFG

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
gingival epithelium	1
jejunal mucosa	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TFG	288	ubiquitous	marker	secondary oocyte, jejunal mucosa, gingival epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TFG	674

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TFG	Q92734	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
Signaling by ALK in cancer	1	271.9×	0.023	TFG
COPII-mediated vesicle transport	1	163.1×	0.023	TFG
Signaling by ALK fusions and activated point mutants	1	150.3×	0.023	TFG
ER to Golgi Anterograde Transport	1	132.8×	0.023	TFG
Transport to the Golgi and subsequent modification	1	102.9×	0.023	TFG
Asparagine N-linked glycosylation	1	60.1×	0.030	TFG
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.030	TFG
Membrane Trafficking	1	37.1×	0.038	TFG
Vesicle-mediated transport	1	34.8×	0.038	TFG
Post-translational protein modification	1	19.2×	0.063	TFG
Disease	1	13.1×	0.081	TFG
Metabolism of proteins	1	12.4×	0.081	TFG

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
COPII vesicle coat assembly	1	702.2×	0.004	TFG
endoplasmic reticulum to Golgi vesicle-mediated transport	1	135.9×	0.011	TFG
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.014	TFG

Therapeutics

Drug target analysis

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

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
TFG	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TFG	2	Binding:2

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	TFG

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)
TFG	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.