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:
The literature predicts a toxic gain-of-function mechanism for HMSN-Okinawa Type: the recurrent dominant TFG p.Pro285Leu variant increases the protein's propensity to self-aggregate into insoluble inclusions and impair the proteasome, a novel toxic species rather than reduced ER-to-Golgi trafficking activity. Because the pathology is driven by acquired aggregation, added wild-type is not predicted to rescue, distinct from haploinsufficiency, though co-aggregation with wild-type keeps confidence at medium.

Rationale:
The recurrent dominant TFG p.Pro285Leu acts by toxic aggregation, and the separate recessive biallelic loss-of-function phenotype argues against haploinsufficiency, so added wild-type is not predicted to rescue: a neomorphic gain of function. Because TFG self-assembles, a dominant-negative co-aggregation cannot be excluded, holding confidence at medium.

ClinVar Pathogenic Variants

View HMSN-Okinawa Type ClinVar Variants

HMSN-Okinawa Type OMIM Entry

HMSN-Okinawa Type OMIM

TFG OMIM Entry

TFG OMIM