Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, 35016 Las Palmas de Gran Canaria, Spain.
Departamento de Bioquímica y Biología Molecular, Instituto Biofisika (UPV/EHU, CSIC), Universidad del País Vasco UPV/EHU, Bilbao, 48940 Leioa, Spain.
Int J Mol Sci. 2023 Jul 11;24(14):11319. doi: 10.3390/ijms241411319.
The p.(Tyr400_Phe402del) mutation in the LDL receptor () gene is the most frequent cause of familial hypercholesterolaemia (FH) in Gran Canaria. The aim of this study was to determine the age and origin of this prevalent founder mutation and to explore its functional consequences. For this purpose, we obtained the haplotypic information of 14 microsatellite loci surrounding the mutation in one homozygous individual and 11 unrelated heterozygous family trios. Eight different mutation carrier haplotypes were identified, which were estimated to originate from a common ancestral haplotype 387 (110-1572) years ago. This estimation suggests that this mutation happened after the Spanish colonisation of the Canary Islands, which took place during the fifteenth century. Comprehensive functional studies of this mutation showed that the expressed LDL receptor was retained in the endoplasmic reticulum, preventing its migration to the cell surface, thus allowing us to classify this mutation as a class 2a, defective, pathogenic variant.
LDL 受体基因中的 p.(Tyr400_Phe402del) 突变是加那利群岛家族性高胆固醇血症 (FH) 最常见的原因。本研究旨在确定这种常见的突变的起源和年龄，并探索其功能后果。为此，我们在一位纯合子个体和 11 个无关的杂合家系三人组中获得了突变周围 14 个微卫星位点的单倍型信息。鉴定出了 8 种不同的突变载体单倍型，估计它们起源于一个共同的祖先单倍型 387（110-1572）年前。这一估计表明，这种突变发生在 15 世纪西班牙对加那利群岛的殖民之后。对该突变的综合功能研究表明，表达的 LDL 受体被保留在内质网中，阻止其向细胞表面迁移，从而使我们能够将这种突变归类为 2a 类，有缺陷的致病性变体。
