Autosomal Recessive Hypercholesterolemia Caused by Mutations in a Putative LDL Receptor Adaptor Protein
Abstract
Atherogenic low density lipoproteins are cleared from the circulation by hepatic low density lipoprotein receptors (LDLR). Two inherited forms of hypercholesterolemia result from loss of LDLR activity: autosomal dominant familial hypercholesterolemia (FH), caused by mutations in the LDLR gene, and autosomal recessive hypercholesterolemia (ARH), of unknown etiology. Here we map the ARH locus to a ∼1-centimorgan interval on chromosome 1p35 and identify six mutations in a gene encoding a putative adaptor protein (ARH). ARH contains a phosphotyrosine binding (PTB) domain, which in other proteins binds NPXY motifs in the cytoplasmic tails of cell-surface receptors, including the LDLR. ARH appears to have a tissue-specific role in LDLR function, as it is required in liver but not in fibroblasts.
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The PTB domains of ARH and DAB1 form an important structural determinant for binding LDLR family members.
“The PTB domains of the adaptor proteins ARH and DAB1 form an important structural determinant for binding LDLR family members (6, 15).”
IDOL interacts with the LDLR at or near the plasma membrane.
“As such, the straightforward interpretation of this result is that IDOL interacts with the LDLR at or near the plasma membrane, akin to other adaptor proteins like DAB1 and ARH involved in receptor endocytosis (6,30,31).”
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- Authors
- Garcia, C. K., Wilund, K., Arca, M., Zuliani, G., Fellin, R., Maioli, M., Calandra, S., Bertolini, S., Cossu, F., Grishin, N., Barnes, R., Cohen, J. C., & Hobbs, H. H.
- Affiliations
- McDermott Center for Human Growth and Development and Department of Internal Medicine and
- Sapienza University of Rome (IT)
- University of Ferrara (IT)
- University of Sassari (IT)
- University of Modena and Reggio Emilia (IT)
- University of Genoa (IT)
- Ospedale Microcitemico (IT)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Hobbs, Helen H.
- ORCID
- Venue
- Science
- Published
- 2001-05-18
- Volume
- 292
- Issue
- 5520
- Pages
- 1394-1398
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2158340752
- Cited by
- 624
- References
- 2
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 16 · 2023: 29 · 2022: 23 · 2021: 28 · 2020: 24 · 2019: 22 · 2018: 27 · 2017: 28 · 2016: 30 · 2015: 21 · 2014: 28 · 2013: 23 · 2012: 31
- FWCI
- 36.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32HL007360, HL 07360, P0I-HL2048)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- autosomal recessive hypercholesterolemia, LDL receptor, phosphotyrosine binding domain, familial hypercholesterolemia, gene mapping, liver-specific function, fibroblasts
- MeSH terms
- Adolescent, Adult, Amino Acid Sequence, Binding Sites, Carrier Proteins, Child, Child, Preschool, Chromosome Mapping, Chromosomes, Human, Pair 1, Cloning, Molecular, Exons, Female, Fibroblasts, Genes, Recessive, Homozygote, Humans, Hypercholesterolemia, Introns, Italy, Lebanon, Liver, Male, Middle Aged, Molecular Sequence Data, Mutation, Organ Specificity, Pedigree, Protein Binding, Receptors, LDL, RNA, Messenger, Sequence Alignment, Phosphotyrosine, Two-Hybrid System Techniques
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