SMA-LEP-2A

Genetic Context

HGNC-Approved Gene Symbol

BICD2

Gene Full Name

BICD cargo adaptor 2

Chromosome

9q22.31

Zygosity of Responsible Variant

Heterozygous

Variant Mechanism

Toxic Gain of Function (GoF)

Details

Mechanistic basis:
Overactivity

Confidence:
Medium

Prediction:
Functional studies predict a gain-of-function mechanism for SMA-LEP-2A: recurrent heterozygous BICD2 substitutions in the N-terminal coiled-coil, p.Ser107Leu foremost among them, weaken the adaptor's closed conformation and increase how readily it recruits and activates dynein-dynactin. Cells expressing the mutant show altered Golgi morphology and disturbed minus-end transport, matching a childhood-onset picture of lower-limb-predominant weakness. The mutant adaptor is overactive in its own right, which separates this mechanism from reduced BICD2 dosage.

Rationale:
Enhanced dynein-dynactin recruitment by the mutant adaptor is measurable without any contribution from the normal allele, which is what distinguishes overactivity from interference. Reports that some BICD2 substitutions instead reduce cargo binding keep the mechanism under active argument, and confidence reflects that split rather than any doubt that the disease is dominant.

ClinVar Pathogenic Variants

View BICD2 ClinVar Variants

SMA-LEP-2A OMIM Entry

SMA-LEP-2A OMIM

BICD2 OMIM Entry

BICD2 OMIM