Disease relevance of LDLRAP1

• PURPOSE OF REVIEW: Autosomal recessive hypercholesterolemia (ARH) is a rare Mendelian dyslipidemia characterized by markedly elevated plasma LDL levels, xanthomatosis, and premature coronary artery disease [1].
• Mutations in the phosphotyrosine-binding domain protein ARH cause autosomal recessive hypercholesterolemia (ARH), an inherited form of hypercholesterolemia due to a tissue-specific defect in the removal of low density lipoproteins (LDL) from the circulation [2].
• The absence of vertical transmission, and the presence of mild coronary heart disease and consanguinity, can suggest a possible diagnosis of ARH [3].
• To investigate the role of MIP-1alpha in MM bone disease in vivo, the human MM-derived cell line ARH was stably transfected with an antisense construct to MIP-1alpha (AS-ARH) and tested for its capacity to induce MM bone disease in SCID mice [4].
• The following associations were found when comparing the active groups with CPTH: 1) ARH: asthma and hypertension; 2) CM: allergies, asthma, hypothyroidism, hypertension, and daily consumption of caffeine; and 3) NDPH: allergies, asthma, hypothyroidism, and consumption of alcohol more than three times per week [5].

Psychiatry related information on LDLRAP1

• Food deprivation caused a decrease in sexual receptivity and in the number of detectable PRIR cells in the MPO and medial amygdala but had no effect on the number of detectable PRIR cells in the VMH/VLH, the ARH, or the anteroventral periventricular nucleus [6].
• The ARH and CM groups had a higher number of subjects with T-scores > or =65, when compared to the migraine group, on the following scales: 1 (hypochondrias), 2 (depression), 8 (schizophrenia) and 0 (social introversion) [7].

High impact information on LDLRAP1

• Components of this disulfide linked heterodimeric complex, Ig-alpha and Ig-beta, contain an approximately 26 residue sequence motif termed ARH1, also known as TAM, which binds to cytoplasmic effectors, including src-family tyrosine kinases, and contains all structural information needed for signal transduction [8].
• ARH appears to have a tissue-specific role in LDLR function, as it is required in liver but not in fibroblasts [9].
• Here we map the ARH locus to an approximately 1-centimorgan interval on chromosome 1p35 and identify six mutations in a gene encoding a putative adaptor protein (ARH) [9].
• Retroviral expression of normal human ARH1 restores LDL receptor internalization in transformed lymphocytes from an affected individual, as demonstrated by uptake and degradation of (125)I-labeled LDL and confocal microscopy of cells labeled with anti-LDL-receptor Ab [10].
• Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: a clinical and molecular genetic analysis [11].

Chemical compound and disease context of LDLRAP1

• The effects of LDL-apheresis with whole blood adsorption were compared in five patients with severe familial and ARH hypercholesterolemia, using two different sorbents, polyacrylic acid with the DALI system and dextran sulfate with the DX21 system [12].
• Basal GR gene expression was not altered by antecedent hypoglycemia, but tissue transcript levels were elevated in the DMH, PVH, VMH, and ARH during RIIH [13].
• Binding assays indicated that 48-h food deprivation decreased progestin receptor levels in the preoptic area and had no effect in the mediobasal hypothalamus, an area that includes the VMH and the arcuate nucleus (ARH) [6].
• Monoclonal antibody HBCA-12 obtained by hybridoma procedure after immunization with human mammary adenocarcinoma cell line MDA-MB-231 immunoprecipitated a cell surface sialoglycoprotein gp80 (apparent molecular weight 80 000) from MDA-MB-231 cells and a glycoprotein gp78 from human myeloma cell line ARH 77 [14].

Biological context of LDLRAP1

• To examine the function of ARH, we used pull-down experiments to test for interactions between ARH, the LDLR, and proteins involved in clathrin-mediated endocytosis [15].
• Recently, the disorder was shown to be caused by mutations in a phosphotyrosine binding domain protein, ARH, which is required for internalization of low density lipoproteins in the liver [1].
• This review summarizes the findings of new investigations into the pathophysiology and molecular genetics of ARH [1].
• The only mutation identified in the remaining proband was a SINE VNTR Alu (SVA) retroposon insertion in intron 1, which was associated with no detectable ARH mRNA [2].
• Direct sequencing of ARH gene demonstrated the presence of a 432insA mutation in homozygosis in the two probands; parents were heterozygotes for the same mutation [16].

Anatomical context of LDLRAP1

• LDL receptor function is normal, or only moderately impaired in fibroblasts from ARH patients, but their cultured lymphocytes show increased cell-surface LDL binding, and impaired LDL degradation, consistent with a defect in LDL receptor internalization [1].
• We described previously two families with autosomal recessive hypercholesterolemia that is not due to mutations in the LDL receptor gene but is characterized by defective LDL receptor-dependent internalization and degradation of LDL by transformed lymphocytes from the patients [10].
• To determine the physiological relevance of these interactions, we examined the effect of mutations in the ARH on LDLR location and function in polarized hepatocytes (WIF-B) [17].
• On internalization of megalin, ARH and megalin are first seen in clathrin coated pits followed by sequential localization in early endosomes and tubular recycling endosomes in the pericentriolar region followed by their reappearance at the cell surface [18].
• At steady state, ARH colocalizes with endocytic proteins in HeLa cells, and the LDL receptor fluxes through peripheral ARH-positive sites before delivery to early endosomes [19].

Associations of LDLRAP1 with chemical compounds

• Mutation of a glutamic acid residue in the appendage domain of beta(2)-adaptin that is required for interaction with the adapter protein beta-arrestin markedly reduced binding to ARH [15].
• Interestingly, ARH is caused by a mutation of cytosine to adenine at this same position [20].
• In ARH plasma LDL cholestrol (LDL-C) level (14.25+/-2.29mmol/L) was lower than in receptor-negative HoFH (21.38+/-3.56mmol/L) but similar to that found in receptor-defective HoFH (15.52+/-2.39mmol/L) [21].
• Combination therapy with high-dose statin and ezetimibe seems to be the treatment of choice in ARH and may reduce or eliminate the need for LDL apheresis treatment [22].
• ARH missense polymorphisms and plasma cholesterol levels [23].

Physical interactions of LDLRAP1

• Mutations in the NPVY sequence that were previously shown to decrease LDLR internalization abolished in vitro binding to ARH [15].
• A highly conserved 20-amino acid sequence in the C-terminal region of ARH bound the beta(2)-adaptin subunit of AP-2 [15].

Regulatory relationships of LDLRAP1

• Autosomal recessive hypercholesterolemia protein interacts with and regulates the cell surface level of Alzheimer's amyloid beta precursor protein [24].

Other interactions of LDLRAP1

• SUMMARY: The available data suggest that ARH functions as an adaptor protein that couples LDLR to the endocytic machinery [1].
• GST-pulldown experiments indicate that the phosphotyrosine binding domain of ARH interacts with the internalization sequence (NPVY) in the cytoplasmic tail of LDLR, and that conserved motifs in the C-terminal portion of the protein bind to clathrin and to the beta2-adaptin subunit of AP-2 [1].
• The interaction between ARH and clathrin was mapped to a canonical clathrin box sequence (LLDLE) in ARH and to the N-terminal domain of the clathrin heavy chain [15].
• However, Dab2 expression is exceptionally low in hepatocytes, likely accounting for the pathological hypercholesterolemia that accompanies ARH loss [25].
• LDL and GPCRs are internalized by ARH and beta-arrestin, respectively [26].

Analytical, diagnostic and therapeutic context of LDLRAP1

• Parallel studies performed in vivo with the same recombinant forms of ARH in livers of Arh(-/-) mice confirmed the relevance of the cell culture findings [17].
• Functional dissection of an AP-2 beta2 appendage-binding sequence within the autosomal recessive hypercholesterolemia protein [27].
• Sequence analysis of the ARH gene (1p35 locus) revealed that the affected siblings are homozygous for a novel mutation (IVS4+2T>G) affecting the donor splice site in intron 4, whereas both the parents and an unaffected sister are heterozygous for this mutation [28].
• All of the ARH homozygotes had large tendinous xanthomas, two had exertional angina, and four a positive stress ECG [3].
• METHODS: We obtained detailed medical histories, did physical examinations, measured concentrations of lipoproteins, and harvested genomic DNA from 28 Sardinians with ARH from 17 unrelated families [11].

References