Carmen Rodríguez-Jiménez1, Diego Gómez-Coronado2, Manuel Frías Vargas3, Francisca Cerrato4, Carlos Lahoz5, Jose Saban-Ruiz6, Daniel González-Nieto7, Miguel A Lasunción2, José M Mostaza5, Sonia Rodríguez-Nóvoa8. 1. Department of Genetics of Metabolic Diseases, Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Madrid, Spain. 2. Department of Biochemistry-Research, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain; CIBER de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Spain. 3. Comillas Primary Care Centre, Madrid, Spain. 4. Department of Biochemistry-Research, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain. 5. Department of Internal Medicine, Hospital Carlos III-La Paz, Madrid, Spain. 6. Endothelium and Cardiometabolic Medicine Unit, Department of Internal Medicine, Hospital Universitario Ramón y Cajal, Madrid, Spain. 7. Center for Biomedical Technology, Photonics Technology and Bioengineering Department, ETSI Telecomunicaciones, Universidad Politécnica de Madrid, and CIBERBBN, Spain. 8. Department of Genetics of Metabolic Diseases, Institute of Medical & Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Madrid, Spain. Electronic address: soniamaria.rodriguez@salud.madrid.org.
Abstract
BACKGROUND AND AIMS: Autosomal recessive hypercholesterolemia (ARH) is a rare disorder caused by mutations in LDLRAP1, which impairs internalization of hepatic LDL receptor (LDLR). ARH patients respond relatively well to statins or the combination of statins and Ezetimibe, but scarce and variable data on treatment with PCSK9 inhibitors is available. We aimed to identify and characterize the defect in a hypercholesterolemic patient with premature cardiovascular disease and determine the response to lipid-lowering treatment. METHODS AND RESULTS: Gene sequencing revealed a homozygous c.1A > G:p.? variant in LDLRAP1. Primary lymphocytes were isolated from the ARH patient, one control and two LDLR-defective subjects, one LDLR:p.(Cys352Ser) heterozygote and one LDLR:p.(Asn825Lys) homozygote. The patient had undetectable full-length ARH protein by Western blotting, but expressed a lower-than-normal molecular weight peptide. LDLR activity was measured by flow cytometry, which showed that LDL binding and uptake were reduced in lymphocytes from the ARH patient as compared to control lymphocytes, but were slightly higher than in those from the LDLR:p.(Cys352Ser) heterozygote. Despite the analogous internalization defect predicted in ARH and homozygous LDLR:p.(Asn825Lys) lymphocytes, LDL uptake was higher in the former than in the latter. LDL-cholesterol levels were markedly reduced by the successive therapy with Atorvastatin and Atorvastatin plus Ezetimibe, and the addition of Evolocumab biweekly decreased LDL-cholesterol by a further 39%. CONCLUSIONS: The LDLRAP1:c.1A > G variant is associated with the appearance of an N-terminal truncated ARH protein and to reduced, although still significant, LDLR activity in lymphocytes. Residual LDLR activity may be relevant for the substantial response of the patient to Evolocumab.
BACKGROUND AND AIMS: Autosomal recessive hypercholesterolemia (ARH) is a rare disorder caused by mutations in LDLRAP1, which impairs internalization of hepatic LDL receptor (LDLR). ARHpatients respond relatively well to statins or the combination of statins and Ezetimibe, but scarce and variable data on treatment with PCSK9 inhibitors is available. We aimed to identify and characterize the defect in a hypercholesterolemicpatient with premature cardiovascular disease and determine the response to lipid-lowering treatment. METHODS AND RESULTS: Gene sequencing revealed a homozygous c.1A > G:p.? variant in LDLRAP1. Primary lymphocytes were isolated from the ARHpatient, one control and two LDLR-defective subjects, one LDLR:p.(Cys352Ser) heterozygote and one LDLR:p.(Asn825Lys) homozygote. The patient had undetectable full-length ARH protein by Western blotting, but expressed a lower-than-normal molecular weight peptide. LDLR activity was measured by flow cytometry, which showed that LDL binding and uptake were reduced in lymphocytes from the ARHpatient as compared to control lymphocytes, but were slightly higher than in those from the LDLR:p.(Cys352Ser) heterozygote. Despite the analogous internalization defect predicted in ARH and homozygous LDLR:p.(Asn825Lys) lymphocytes, LDL uptake was higher in the former than in the latter. LDL-cholesterol levels were markedly reduced by the successive therapy with Atorvastatin and Atorvastatin plus Ezetimibe, and the addition of Evolocumab biweekly decreased LDL-cholesterol by a further 39%. CONCLUSIONS: The LDLRAP1:c.1A > G variant is associated with the appearance of an N-terminal truncated ARH protein and to reduced, although still significant, LDLR activity in lymphocytes. Residual LDLR activity may be relevant for the substantial response of the patient to Evolocumab.
Authors: Ane Bayona; Francisco Arrieta; Carmen Rodríguez-Jiménez; Francisco Cerrato; Sonia Rodríguez-Nóvoa; Milagros Fernández-Lucas; Diego Gómez-Coronado; Pedro Mata Journal: Medicine (Baltimore) Date: 2020-08-21 Impact factor: 1.817