dHMN-5B

Genetic Context

HGNC-Approved Gene Symbol

REEP1

Gene Full Name

receptor accessory protein 1

HGNC Gene Alias(es)

C2ORF23

Chromosome

2p11.2

Zygosity of Responsible Variant

Heterozygous

Mitochondrial Involvement

Yes

Variant Mechanism

Loss of Function (LoF)

Details

Mechanistic basis:
Haploinsufficiency

Confidence:
Medium

Prediction:
Evidence across REEP1 families predicts a haploinsufficiency mechanism for dHMN-5B: most dominant alleles are truncating variants or whole-exon deletions whose transcripts are cleared by nonsense-mediated decay, leaving a single working copy of a dosage-sensitive ER-shaping and microtubule-interacting protein, and Reep1-null models show the expected axonal degeneration. Loss of the same gene also causes SPG31, a dominant hereditary spastic paraplegia, so half-normal REEP1 is on its own enough to injure long axons.

Rationale:
Nonsense-mediated decay of the common truncating alleles removes protein instead of producing a mutant that could act on its partner, and tubular ER morphology depends on REEP1 concentration, which is why one intact copy falls short. C-terminal variants that escape decay may add a toxic component, and that open question leaves the mechanism graded medium.

ClinVar Pathogenic Variants

View REEP1 ClinVar Variants

dHMN-5B OMIM Entry

dHMN-5B OMIM

REEP1 OMIM Entry

REEP1 OMIM