title: Identification of a recurrent frameshift mutation at the LDLR exon 14 (c.2027delG, p.(G676Afs*33)) causing familial hypercholesterolemia in Saudi Arab homozygous children.
abstract: Familial hypercholesterolemia (FH) is an autosomal dominant disease, predominantly caused by variants in the low-density lipoprotein (LDL) receptor gene (LDLR). Herein, we describe genetic analysis of severely affected homozygous FH patients who were mostly resistant to statin therapy and were managed on an apheresis program. We identified a recurrent frameshift mutation p.(G676Afs*33) in exon 14 of the LDLR gene in 9 probands and their relatives in an apparently unrelated Saudi families. We also describe a three dimensional homology model of the LDL receptor protein (LDLR) structure and examine the consequence of the frameshift mutation p.(G676Afs*33), as this could affect the LDLR structure in a region involved in dimer formation, and protein stability. This finding of a recurrent mutation causing FH in the Saudi population could serve to develop a rapid genetic screening procedure for FH, and the 3D-structure analysis of the mutant LDLR, may provide tools to develop a mechanistic model of the LDLR function.
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia; Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia; Molecular Diagnostics Unit, Department of Laboratory and Blood Bank, King Abdullah Medical City, Makkah, Saudi Arabia. Electronic address: fallaf@uqu.edu.sa.
authors.forename: Faisal A
authors.initials: FA
authors.lastname: Al-Allaf
authors.affiliation: King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Alashwal
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia; Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Zainularifeen
authors.initials: Z
authors.lastname: Abduljaleel
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia; Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Mohiuddin M
authors.initials: MM
authors.lastname: Taher
authors.affiliation: Department of Oral and Basic Sciences, Faculty of Dentistry, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Shahid S
authors.initials: SS
authors.lastname: Siddiqui
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia; Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Abdellatif
authors.initials: A
authors.lastname: Bouazzaoui
authors.affiliation: King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Hala
authors.initials: H
authors.lastname: Abalkhail
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Rakan
authors.initials: R
authors.lastname: Aun
authors.affiliation: Faculty of Medicine, Al-Faisal University, Riyadh, Saudi Arabia.
authors.forename: Ahmad F
authors.initials: AF
authors.lastname: Al-Allaf
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Iman
authors.initials: I
authors.lastname: AbuMansour
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Zohor
authors.initials: Z
authors.lastname: Azhar
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Faisal A
authors.initials: FA
authors.lastname: Ba-Hammam
authors.affiliation: Department of Basic Sciences, College of Science and Health Professions, King Saud Bin Abdul Aziz University for Health Sciences, Riyadh, Saudi Arabia.
authors.forename: Wajahatullah
authors.initials: W
authors.lastname: Khan
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia; Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia. Electronic address: mabedar@uqu.edu.sa.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Athar
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D011973:Receptors, LDL / Q000737:chemistry* / Q000235:genetics
chemical_list: C573412:LDLR protein, human; D011973:Receptors, LDL
keywords: Arab; Atherosclerosis; Cholesterol; Coronary heart diseases (CHD); Familial hypercholesterolemia (FH); Frameshift mutation; Genetics; Low-density lipoprotein receptor (LDLR); MD simulation; PCR; Protein structure; Saudi Arabia