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Autosomal recessive hypercholesterolemia (ARH; MONDO:0011374) is a rare dyslipidemia characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C), tendon and cutaneous xanthomas, hepatic steatosis, and premature atherosclerosis. The disease is caused by biallelic loss-of-function variants in LDLRAP1 (HGNC:18640), which encodes an adaptor protein essential for clathrin-mediated internalization of the LDL receptor (LDLR) in hepatocytes. Carriers of pathogenic LDLRAP1 variants have residual LDLR activity in nonhepatic cells, accounting for a milder phenotype compared to homozygous LDLR deficiency.
ARH follows an autosomal recessive inheritance pattern with segregation of biallelic LDLRAP1 variants in multiple unrelated families. Japanese siblings homozygous for c.603dup (p.Ser202fs) presented with severe hypercholesterolemia, xanthomas, fatty liver, and premature atherosclerosis, with both parents heterozygous (PMID:12788851). A Sardinian cohort comprising 28 ARH probands from 17 unrelated families all carried recurrent frameshift (c.432insA) or nonsense (c.65G>A) mutations, consistent with founder alleles and autosomal recessive segregation (PMID:11897284). Mexican and Lebanese kindreds harboring novel splice-site mutations (IVS4+2T>G; IVS1–1G>C) further corroborate the recessive inheritance and pathogenicity of LDLRAP1 loss-of-function alleles (PMID:15599766; PMID:15485476).
Over 20 distinct biallelic LDLRAP1 variants have been identified, including frameshift, nonsense, and splice-site mutations. The most common alleles are c.431dup (p.His144fs), c.432insA (p.Ala145fs), and c.603dup (p.Ser202fs), observed across multiple ethnicities. Segregation analysis in at least 19 additional affected relatives supports the recessive transmission and high penetrance of these variants.
Biochemical and cellular studies demonstrate that pathogenic LDLRAP1 mutations abrogate full-length ARH protein expression in hepatocytes and lymphocytes, impairing LDLR clustering in clathrin-coated pits and LDL uptake (PMID:12221107). In vitro pull-down assays confirm ARH binding to the LDLR NPVY internalization motif, clathrin heavy chain, and AP-2, elucidating the molecular mechanism of ARH as an endocytic adaptor. Patient-specific iPSC-derived hepatocyte-like cells lacking LDLRAP1 recapitulate reduced LDL-C uptake, validating the disease model (PMID:33938231).
The association of LDLRAP1 with ARH meets ClinGen Definitive criteria: over 30 probands from >17 unrelated families with consistent autosomal recessive segregation, recurrent loss-of-function variants, and concordant functional data. The gene–disease relationship has been replicated over >20 years with no credible conflicting evidence.
Key Take-Home: LDLRAP1 loss-of-function variants cause definitively autosomal recessive hypercholesterolemia, and genetic testing for biallelic LDLRAP1 mutations informs diagnosis, family screening, and tailored lipid-lowering therapy.
Gene–Disease AssociationDefinitiveMore than 30 probands from >17 unrelated families, consistent autosomal recessive segregation, and concordant functional data Genetic EvidenceStrong30 ARH cases with biallelic LDLRAP1 variants across 20 families and recurrent LoF mutations Functional EvidenceModerateIn vitro assays demonstrate absence of LDLRAP1 protein, impaired LDLR internalization, and validated iPSC hepatocyte-like cell models |