CMT2A2B

Genetic Context

HGNC-Approved Gene Symbol

MFN2

Gene Full Name

mitofusin 2

HGNC Gene Alias(es)

CPRP1, KIAA0214, MARF

Chromosome

1p36.22

Zygosity of Responsible Variant

Homozygous or Compound Heterozygous

Mitochondrial Involvement

Yes

Variant Mechanism

Loss of Function (LoF)

Details

Mechanistic basis:
Hypomorphic

Confidence:
Medium

Prediction:
The literature predicts a biallelic loss-of-function mechanism for CMT2A2B: mitofusin-2 tethers outer mitochondrial membranes for fusion, and the recessive MFN2 genotypes combine alleles that lower that activity rather than abolish it, with heterozygous relatives unaffected. Complete mitofusin-2 loss is not compatible with this phenotype, since Mfn2-null mice die in midgestation and near-null human genotypes present as lethal neonatal disease, so at least one partial-function allele is required.

Rationale:
These families sit at a threshold rather than at zero: enough fusion activity survives to carry development, and too little survives to maintain the longest axons into adult life. Homozygous p.Arg707Trp is the recurring genotype, a reduced-function allele rather than a null. Nothing here is positioned to act on a wild-type partner, which is what separates this from the dominant MFN2 subtype.

ClinVar Pathogenic Variants

View MFN2 ClinVar Variants

ClinGen Curation

View MFN2 ClinGen Curation

GeneReviews®

CMT2A2B GeneReviews®

CMT2A2B OMIM Entry

CMT2A2B OMIM

MFN2 OMIM Entry

MFN2 OMIM