{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T17:18:23Z","timestamp":1780507103176,"version":"3.54.1"},"reference-count":79,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T00:00:00Z","timestamp":1767571200000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100019706","name":"Qatar Biomedical Research Institute, Hamad Bin Khalifa University","doi-asserted-by":"publisher","award":["QB35"],"award-info":[{"award-number":["QB35"]}],"id":[{"id":"10.13039\/100019706","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Familial hypercholesterolemia (FH) is a genetic disorder characterised by elevated plasma LDL\u2010cholesterol, predisposing to premature atherosclerotic cardiovascular disease. Most cases follow an autosomal dominant pattern (ADH) caused by pathogenic variants in\n                    <jats:italic>LDLR, APOB or PCSK9<\/jats:italic>\n                    . In contrast, the rare autosomal recessive form (ARH) results from biallelic mutations in\n                    <jats:italic>LDLRAP1<\/jats:italic>\n                    , leading to defective LDL receptor\u2010mediated endocytosis. Despite the high rate of consanguinity in Tunisia,\n                    <jats:italic>LDLRAP1<\/jats:italic>\n                    variants have not yet been reported in this population. In this study, Whole Exome Sequencing of two consanguineous Tunisian families, identified distinct pathogenic variants. In the first family (FH\u2010A), a recurrent\n                    <jats:italic>LDLR<\/jats:italic>\n                    splice\u2010site variant (c.1845+1G&gt;A) was detected in both heterozygous and homozygous states, consistent with an autosomal dominant inheritance pattern. In the second family (FH\u2010B), a novel homozygous\n                    <jats:italic>LDLRAP1<\/jats:italic>\n                    missense variant (c.161G&gt;A; p.Gly54Asp) was identified, confirming autosomal recessive inheritance.\n                    <jats:italic>In silico<\/jats:italic>\n                    analyses using MutationTaster, DynaMut2, MUpro, DDGun, NetSurfP\u20102.0, ConSurf and PyMOL predicted that the p.Gly54Asp substitution destabilises the PTB domain of LDLRAP1 by disrupting key hydrogen bonds and hydrophobic interactions, thereby likely impairing LDLR internalisation. According to ACMG guidelines, this variant is classified as likely pathogenic. Clinically, ARH patients exhibited early\u2010onset xanthomas and an unusual quadricuspid aortic valve (QAV). Targeted analysis of valvulogenesis genes (\n                    <jats:italic>NOTCH1, GATA4, NKX2\u20105, TBX5, AGTR1, BMP2<\/jats:italic>\n                    ) revealed no co\u2010segregating pathogenic variants, suggesting that QAV may result from embryonic LDL accumulation disrupting\n                    <jats:italic>Notch1<\/jats:italic>\n                    signalling rather than a monogenic defect. Comparison with other ADH Tunisian families carrying the same\n                    <jats:italic>LDLR<\/jats:italic>\n                    mutation showed phenotypic variability, likely influenced by genetic modifiers, treatment response and environmental factors. These findings provide the first evidence of\n                    <jats:italic>LDLRAP1<\/jats:italic>\n                    \u2010associated ARH in Tunisia and highlight the genetic heterogeneity of FH, emphasising the importance of integrating molecular, structural and functional analyses for accurate diagnosis, personalised management and early prevention.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.70997","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T07:56:58Z","timestamp":1767686218000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["First\n                    <i>LDLRAP1<\/i>\n                    and Recurrent\n                    <i>LDLR<\/i>\n                    Mutations in Tunisian Families With Familial Hypercholesterolemia"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4188-7265","authenticated-orcid":false,"given":"Wirath Ben","family":"Ncir","sequence":"first","affiliation":[{"name":"Laboratory of Human Molecular Genetics Faculty of Medicine of Sfax  Sfax Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afif","family":"Ben\u2010Mahmoud","sequence":"additional","affiliation":[{"name":"Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI) Hamad Bin Khalifa University (HBKU), Qatar Foundation  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamdi","family":"Frikha","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Hedi Chaker Hospital of Sfax  Sfax Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma","family":"Abdelhedi","sequence":"additional","affiliation":[{"name":"Laboratory of Human Molecular Genetics Faculty of Medicine of Sfax  Sfax Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faten Hadj","family":"Kacem","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Hedi Chaker Hospital of Sfax  Sfax Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabila","family":"Majdoub","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Hedi Chaker Hospital of Sfax  Sfax Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mouna","family":"Mnif","sequence":"additional","affiliation":[{"name":"Department of Endocrinology Hedi Chaker Hospital of Sfax  Sfax Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyung\u2010Goo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers The State University of New Jersey  Piscataway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila Ammar","family":"Keskes","sequence":"additional","affiliation":[{"name":"Laboratory of Human Molecular Genetics Faculty of Medicine of Sfax  Sfax Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jouke\u2010Jan","family":"Hottenga","sequence":"additional","affiliation":[{"name":"Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI) Hamad Bin Khalifa University (HBKU), Qatar Foundation  Doha Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,5]]},"reference":[{"issue":"32","key":"e_1_2_13_2_1","doi-asserted-by":"crossref","first-page":"2459","DOI":"10.1093\/eurheartj\/ehx144","article-title":"Low\u2010Density Lipoproteins Cause Atherosclerotic Cardiovascular Disease. 1. Evidence From Genetic, Epidemiologic, and Clinical Studies. A Consensus Statement From the European Atherosclerosis Society Consensus Panel","volume":"38","author":"Ference B. A.","year":"2017","journal-title":"European Heart Journal"},{"key":"e_1_2_13_3_1","unstructured":"P.Hu K. I.Dharmayat C. A. T.Stevens andR. S.Jones \u201cPrevalence of Familial Hypercholesterolemia Among the General Population and Patients With Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta\u2010Analysis \u201d(2020) accessed September 21 2025 https:\/\/pubmed.ncbi.nlm.nih.gov\/32468833\/."},{"issue":"1","key":"e_1_2_13_4_1","doi-asserted-by":"crossref","first-page":"S108","DOI":"10.1016\/j.ihj.2023.12.002","article-title":"Familial Hypercholesterolemia","volume":"76","author":"Sawhney J. P. S.","year":"2024","journal-title":"Indian Heart Journal"},{"issue":"2","key":"e_1_2_13_5_1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1097\/MOL.0000000000000664","article-title":"Autosomal Recessive Hypercholesterolemia: Update for 2020","volume":"31","author":"D'Erasmo L.","year":"2020","journal-title":"Current Opinion in Lipidology"},{"key":"e_1_2_13_6_1","unstructured":"R.Henderson M.O'Kane andV.McGilligan \u201cThe Genetics and Screening of Familial Hypercholesterolaemia \u201d(2016) accessed September 21 2025 https:\/\/pubmed.ncbi.nlm.nih.gov\/27084339\/."},{"issue":"5","key":"e_1_2_13_7_1","first-page":"374","article-title":"A Novel Splice Site Variant in the LDLRAP1 Gene Causes Familial Hypercholesterolemia","volume":"25","author":"Ahangari N.","year":"2021","journal-title":"Iranian Biomedical Journal"},{"issue":"1","key":"e_1_2_13_8_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41569-018-0052-6","article-title":"The Complex Molecular Genetics of Familial Hypercholesterolaemia","volume":"16","author":"Berberich A. J.","year":"2019","journal-title":"Nature Reviews. Cardiology"},{"key":"e_1_2_13_9_1","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.atherosclerosis.2019.01.010","article-title":"A New Variant (c.1A>G) in LDLRAP1 Causing Autosomal Recessive Hypercholesterolemia: Characterization of the Defect and Response to PCSK9 Inhibition","volume":"284","author":"Rodr\u00edguez\u2010Jim\u00e9nez C.","year":"2019","journal-title":"Atherosclerosis"},{"issue":"14","key":"e_1_2_13_10_1","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1089\/scd.2020.0199","article-title":"Patient\u2010Specific Induced Pluripotent Stem Cell\u2010Derived Hepatocyte\u2010Like Cells as a Model to Study Autosomal Recessive Hypercholesterolemia","volume":"30","author":"Nikasa P.","year":"2021","journal-title":"Stem Cells and Development"},{"key":"e_1_2_13_11_1","unstructured":"M.AbifadelandC.Boileau \u201cGenetic and Molecular Architecture of Familial Hypercholesterolemia \u201d(2022) accessed September 21 2025 https:\/\/pubmed.ncbi.nlm.nih.gov\/36196022\/."},{"key":"e_1_2_13_12_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.atherosclerosis.2021.05.007","article-title":"APOE Gene Variants in Primary Dyslipidemia","volume":"328","author":"Khalil Y. A.","year":"2021","journal-title":"Atherosclerosis"},{"key":"e_1_2_13_13_1","unstructured":"F.Civeira \u201cAPOE and Familial Hypercholesterolemia \u201d(2024) accessed September 21 2025 https:\/\/pubmed.ncbi.nlm.nih.gov\/38640077\/."},{"issue":"3","key":"e_1_2_13_14_1","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1097\/MOL.0000000000000926","article-title":"Familial Hypercholesterolemia in Children and the Importance of Early Treatment","volume":"35","author":"Bosch S. E.","year":"2024","journal-title":"Current Opinion in Lipidology"},{"issue":"11","key":"e_1_2_13_15_1","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1007\/s11883-023-01155-6","article-title":"Sex Differences in Familial Hypercholesterolemia","volume":"25","author":"Klevmoen M.","year":"2023","journal-title":"Current Atherosclerosis Reports"},{"issue":"11","key":"e_1_2_13_16_1","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1161\/CIRCULATIONAHA.115.018791","article-title":"Prevalence of Familial Hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES)","volume":"133","author":"De Ferranti S. 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