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Mutation type classification and pathogenicity assignment of sixteen missense variants located in the EGF-precursor homology domain of the LDLR

Galicia-Garcia, Unai, Benito-Vicente, Asier, Uribe, Kepa B., Jebari, Shifa, Larrea-Sebal, Asier, Alonso-Estrada, Rocio, Aguilo-Arce, Joseba, Ostolaza, Helena, Palacios, Lourdes, Martin, Cesar·2020·Scientific Reports
DOI 10.1038/s41598-020-58734-9PMC PMC6997160
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Abstract

The primary genetic cause of familial hypercholesterolemia (FH) is related to mutations in the LDLR gene encoding the Low-density Lipoprotein Receptor. LDLR structure is organized in 5 different domains, including an EGF-precursor homology domain that plays a pivotal role in lipoprotein release and receptor recycling. Mutations in this domain constitute 51.7% of the total missense variants described in LDLR. The aim of the present work was to analyse how clinically significant variants in the EGF-precursor homology domain impact LDLR. The activity of sixteen LDLR variants was functionally characterized by determining LDLR expression by Western blot and LDLR expression, LDL binding capacity and uptake, and LDLR recycling activity by flow cytometry in transfected CHO- ldl A7 cells. Of the analysed variants, we found six non-pathogenic LDLR variants and ten pathogenic variants distributed as follow: three class 3 variants; four class 2 variants; and three class 5 variants. These results can be incorporated into clinical management of patients by helping guide the appropriate level of treatment intensity depending on the extent of loss of LDLR activity. This data can also contribute to cascade-screening for pathogenic FH variants.

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  • Complete absence or defective LDLRs due to mutations in the LDLR gene cause familial hypercholesterolemia, characterized by autosomal dominant inheritance of hypercholesterolemia and premature atherosclerotic cardiovascular disease.

    “Complete absence or defective LDLRs due to mutations in the LDLR gene cause FH, characterized by an autosomal dominant inheritance of hypercholesterolemia and premature ASCVD (a list of mutations can be found in Table 1)1–4.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [1]

    The Introduction (page not provided) says LDLR mutations account for approximately 80–85% of FH cases, describes mutations that eliminate or impair receptor function, and links FH to high LDL cholesterol and premature atherosclerotic disease. Our copy does not state that FH has autosomal dominant inheritance, so that part of the claim is not supported by this source. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Of LDLR mutations, all result in familial hypercholesterolemia, and most result in loss of LDLR function, either through complete loss of protein or production of a modified nonfunctional protein.

    “Of these mutations, all result in FH, and most result in loss of LDLR function, either through complete loss of protein or production of a modified protein which is nonfunctional.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [1]

  • Class V LDLR mutations allow LDLR to bind cargo for internalization but with weak affinity or inability to release cargo once internalized, prompting protein turnover.

    “The exception to this are Class V mutations where LDLR can still bind cargo for internalization, but binds with weak affinity or cannot release the cargo once internalized, prompting protein turnover1.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [1]

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Research works printed but not linked: 31

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Metadata

Authors
Galicia-Garcia, U., Benito-Vicente, A., Uribe, K. B., Jebari, S., Larrea-Sebal, A., Alonso-Estrada, R., Aguilo-Arce, J., Ostolaza, H., Palacios, L., & Martin, C.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2020-02-03
Volume
10
Issue
1
ISSN
2045-2322
DOI
10.1038/s41598-020-58734-9
PMC
PMC6997160
Cited by
44
References
1
Language
en
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