CMT-ABHD12

Genetic Context

HGNC-Approved Gene Symbol

ABHD12

Gene Full Name

abhydrolase domain containing 12, lysophospholipase

Chromosome

20p11.21

Zygosity of Responsible Variant

Homozygous or Compound Heterozygous

Variant Mechanism

Loss of Function (LoF)

Details

Mechanistic basis:
Complete loss

Confidence:
High

Prediction:
Published evidence points to a biallelic loss-of-function mechanism for CMT-ABHD12: nonsense, frameshift, splice, and missense variants inactivate the serine hydrolase that clears lysophosphatidylserine, and the disease emerges as that signaling lipid accumulates in nervous tissue. The Abhd12 knockout mouse reproduces the lysophosphatidylserine build-up together with progressive auditory and motor decline, and carriers of a single inactive allele remain well, so disease requires both copies to fail.

Rationale:
Without functional ABHD12 the damage comes from the substrate, not from a mutant product: lysophosphatidylserine is an immune signaling lipid, and its accumulation provokes the neuroinflammatory and degenerative changes seen in the knockout mouse and in the PHARC phenotype of polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract. Returning hydrolase activity addresses the primary lesion.

ClinVar Pathogenic Variants

View ABHD12 ClinVar Variants

CMT-ABHD12 OMIM Entry

CMT-ABHD12 OMIM

ABHD12 OMIM Entry

ABHD12 OMIM