HMSN-Okinawa Type

Genetic Context

HGNC-Approved Gene Symbol

TFG

Gene Full Name

trafficking from ER to golgi regulator

Chromosome

3q12.2

Zygosity of Responsible Variant

Heterozygous

Variant Mechanism

Toxic Gain of Function (GoF)

Details

Mechanistic basis:
Neomorphic

Confidence:
Medium

Prediction:
Evidence in HMSN-Okinawa Type predicts a toxic gain of function: the recurrent heterozygous TFG p.Pro285Leu substitution sits in the C-terminal low-complexity region and raises the protein's tendency to self-assemble into insoluble cytoplasmic inclusions, with proteasomal handling compromised in affected motor neurons. Biallelic TFG variants instead cause a recessive spastic paraplegia with optic atrophy, so reduced TFG dosage does not account for the proximal-dominant phenotype.

Rationale:
Insoluble inclusions, not diminished ER-exit-site function, dominate the pathology, and the mutant acquires that aggregation property on its own. A separate recessive TFG disease is the strongest argument that losing this protein's activity produces something else entirely. What keeps the mechanism unsettled is TFG's native oligomerization: an aggregating mutant can plausibly draw wild-type subunits in with it.

ClinVar Pathogenic Variants

View TFG ClinVar Variants

HMSN-Okinawa Type OMIM Entry

HMSN-Okinawa Type OMIM

TFG OMIM Entry

TFG OMIM