LDLRAP1 – Homozygous Familial Hypercholesterolemia

Autosomal recessive hypercholesterolemia (ARH) due to biallelic variants in LDLRAP1 presents with markedly elevated low-density lipoprotein cholesterol (LDL-C) and accelerated atherosclerosis indistinguishable from Homozygous Familial Hypercholesterolemia (HoFH).

Inheritance is autosomal recessive, with 53 unrelated homozygous probands reported across large registries and case series: 5 true LDLRAP1 homozygotes in the Spanish Dyslipidemia Registry ([PMID:27784735]), 46 in an Italian cohort of ARH patients ([PMID:32977124]), and 2 siblings carrying c.617-14C>A splicing alleles in a family report ([PMID:39532566]). Segregation analyses demonstrate concordant homozygosity in affected sibships and heterozygous carrier parents, confirming recessive transmission and full phenotypic penetrance in homozygotes.

The variant spectrum is dominated by loss-of-function alleles, including deep-intronic splice site changes (e.g., c.617-14C>A) that abolish exon recognition. Both canonical splice site (c.459+2T>G) and cryptic intronic (c.748-608G>A) mutations have been described, all precluding synthesis of full-length ARH protein. No recurrent founder variants have been observed outside localized clusters.

Functional assays across multiple studies support a loss-of-function mechanism. ARH’s phosphotyrosine-binding domain binds the LDLR NPXY motif, while separate binding sites recruit clathrin and AP-2, coupling LDLR to clathrin-coated pits ([PMID:12221107]). ARH-deficient cells and Arh⁻/⁻ mice show impaired LDLR clustering and uptake, which is restored by wild-type ARH but not by patient-derived mutants ([PMID:12417523]; [PMID:16179341]).

No studies have refuted LDLRAP1’s role in ARH, and no phenotypic heterogeneity beyond classical HoFH has emerged. The integration of robust genetic and functional data supports a Strong ClinGen classification. Genetic testing for LDLRAP1 variants is critical for distinguishing ARH from other HoFH genotypes and guiding early initiation of statin, ezetimibe, or PCSK9 inhibitor therapy.

Key Take-home: LDLRAP1 biallelic loss-of-function variants cause autosomal recessive hypercholesterolemia clinically equivalent to HoFH, warranting inclusion of LDLRAP1 in genetic panels for familial hypercholesterolemia and informing tailored lipid-lowering strategies.

References

• Circulation: Cardiovascular Genetics • 2016 • Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship PMID:27784735
• Atherosclerosis • 2020 • Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features PMID:32977124
• Journal of Clinical Lipidology • 2025 • Rapid lipid-lowering response in two cases of autosomal recessive hypercholesterolemia. PMID:39532566
• The Journal of Biological Chemistry • 2002 • ARH is a modular adaptor protein that interacts with the LDL receptor, clathrin, and AP-2. PMID:12221107
• Human Molecular Genetics • 2002 • Molecular mechanisms of autosomal recessive hypercholesterolemia. PMID:12417523
• The Journal of Biological Chemistry • 2005 • The modular adaptor protein autosomal recessive hypercholesterolemia (ARH) promotes low density lipoprotein receptor clustering into clathrin-coated pits. PMID:16179341

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