HMSN-6A

Genetic Context

HGNC-Approved Gene Symbol

MFN2

Gene Full Name

mitofusin 2

Chromosome

1p36.22

Zygosity of Responsible Variant

Heterozygous

Mitochondrial Involvement

Yes

Variant Mechanism

Dominant-Negative

Details

Confidence:
Medium

Prediction:
The literature predicts a dominant-negative mechanism for HMSN-6A: mitofusin-2 fuses apposed mitochondrial outer membranes only as an oligomer acting in trans, so heterozygous MFN2 missense alleles seed complexes that also contain normal MFN2 and MFN1, blunting fusion and the axonal transport of mitochondria. Wild-type add-back is not predicted to restore fusion in complexes that already hold a mutant subunit. Biallelic MFN2 alleles instead cause a severe early-onset recessive loss-of-function disease. That MFN1 co-expression rescues several mutants in trans keeps the mechanism contested and confidence at medium.

Rationale:
Mutant mitofusin-2 enters the same trans tethering complexes as normal MFN2 and MFN1, and because tethering requires competent oligomers on both membranes, one defective subunit stalls the reaction rather than merely halving capacity. Mitochondria then clump and move poorly along the axon, a deficit the optic nerve and the longest peripheral axons register first.

ClinVar Pathogenic Variants

View MFN2 ClinVar Variants

ClinGen Curation

View MFN2 ClinGen Curation

GeneReviews®

HMSN-6A GeneReviews®

HMSN-6A OMIM Entry

HMSN-6A OMIM

MFN2 OMIM Entry

MFN2 OMIM