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APOA1-related primary hypoalphalipoproteinemia type 2 is an autosomal recessive disorder characterized by severely reduced HDL-cholesterol due to biallelic loss-of-function variants. Three unrelated probands have been reported: a 69-year-old woman with a c.552del (p.Thr185ArgfsTer) frameshift and early stop, a patient with carboxyl-terminal truncation p.His186ProfsTer46, and a homozygous c.322C>T (p.Gln108Ter) nonsense variant, all leading to undetectable apoA-I levels and low HDL (PMID:11996960)(PMID:29396262)(PMID:1901417).
Functional studies in patient plasma, cell models and transgenic mice demonstrate that these truncating mutations abolish apoA-I secretion, impair HDL disc formation, reduce LCAT activation and accelerate apoA-I catabolism, consistent with a haploinsufficiency mechanism (PMID:1898657)(PMID:2111322). No segregation beyond the index cases has been documented, but extensive concordant experimental data support pathogenicity and inform diagnostic decision-making and potential therapeutic targeting.
Key take-home: Biallelic truncating APOA1 variants cause a clinically recognizable AR HDL-deficiency syndrome with robust functional evidence, enabling accurate molecular diagnosis and guiding future intervention trials.
Gene–Disease AssociationLimited3 probands across unrelated families, no segregation, consistent truncating variants Genetic EvidenceLimited3 probands with biallelic truncating LoF variants leading to absent apoA-I levels Functional EvidenceModerateIn vitro and in vivo assays demonstrate impaired secretion, HDL formation, LCAT activation and accelerated catabolism |