Influence of an asparagine to lysine mutation at amino acid 3516 of apolipoprotein B on low-density lipoprotein receptor binding

Gaffney, Dairena; Pullinger, Clive R.; O’Reilly, Denis St. J.; Hoffs, Michael; Cameron, Isobel M.; Vass, J. Keith; Kulkarni, Medha V.; Kane, John P.; Schumaker, Verne N.; Watts, Gerald F.

doi:10.1016/s0009-8981(02)00106-7

Cited by 12 publications

(5 citation statements)

References 31 publications

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“…This new molecular disorder was called Familial ligand-Defective apolipoprotein B-100 (FDB, MIM# 144010). Only five hypercholesterolemic mutations of the APOB gene have been reported to date (Soria et al, 1989;Gaffney et al, 1995;Boren et al, 2001;Gaffney et al, 2002;Soufi et al, 2004). Recently, our team identified involvement of a third gene in ADH: the PCSK9 gene (NM_174936; MIM# 603776; 607786) at 1p34-p32.…”

Section: Introductionmentioning

confidence: 99%

Novel mutations of thePCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia

et al. 2005

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Autosomal dominant hypercholesterolemia (ADH) is a frequent (1/500) monogenic inherited disorder characterized by isolated elevation of LDL leading to premature cardiovascular disease. ADH is known to result from mutations at two main loci: LDLR (encoding the low density lipoprotein receptor), and APOB (encoding apolipoprotein B100), its natural ligand. We previously demonstrated that ADH is also caused by mutations of the PCSK9 (proprotein convertase subtilisin/kexin type 9) gene that encodes Narc-1 (neural apoptosis-regulated convertase 1). However, the role of this novel disease locus as a cause of hypercholesterolemia remains unclear. In the present study, we analysed the PCSK9 coding region and intronic junctions in 130 adult or pediatric patients with ADH, previously found as being non LDLR/non APOB mutation carriers. Four novel heterozygous missense variations were found: c.654A>T (p.R218S), c.1070G>A (p.R357H), c.1405C>T (p.R469W), and c.1327G>A (p.A443T). All mutations were absent in 340 normolipidemic controls. Except for the A443T, all mutations are nonconservative and modify a highly conserved residue. Segregation with hypercholesterolemia is incomplete in one pedigree. Type and severity of hyperlipidemia and of cardiovascular disease could vary among subjects from the same family. Finally, the proband carrying the R357H mutation exhibited very high plasma cholesterol during pregnancy, whereas the proband carrying the p.R469W mutation exhibited a severe phenotype of hypercholesterolemia in combination with a LDLR mutation resulting from a frameshift at residue F382 (1209delC). These observations suggest that variations in PCSK9 are a rare cause of non LDLR/non APOB ADH (approximately 2.3%) and that additional environmental or genetic factors may contribute to the phenotype caused by PCSK9 missense mutations in humans.

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Section: Introductionmentioning

confidence: 99%

Novel mutations of thePCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia

et al. 2005

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“…The p.R3480W mutation is also associated with FDB because of its position near tryptophan 4369 that was shown to interact with arginine 3500 and facilitate the conformation of apo B‐100 required for normal receptor binding of LDL (42). The p.N3516K mutation introduces a positively charged amino acid (lysine), while other FDB mutations remove a positively charged residue (arginine) and were shown to influence conformation of LDL apo B and its interaction with the LDL receptor (51). In 2004, Soufi et al screened a German population for the presence of any putative new apo B‐100 mutation within the region of codons 3448–3561 and detected a new single‐base substitution resulting in the p.His3543Tyr mutation (p.H3543Y) (52).…”

Section: Molecular Defectsmentioning

confidence: 99%

Genetic heterogeneity of autosomal dominant hypercholesterolemia

et al. 2007

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Autosomal dominant hypercholesterolemia (ADH) is characterized by isolated elevation of plasmatic low-density lipoprotein cholesterol associated with high risk of premature cardiovascular complications. More than 1000 mutations in the LDLR gene and 9 in the APOB gene have been implicated. We have shown further heterogeneity with the discovery of missense mutations in the PCSK9 gene resulting in ADH. Different studies have tried to evaluate the respective contribution of mutations in each gene to the disease, but results were not always in agreement. After a brief overview of mutations reported for each gene, strategies and results of these different studies are reviewed and analyzed. Altogether, numerous reports give evidence for the existence of a greater level of genetic heterogeneity in ADH and the involvement of still unknown genes.

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“…Asparagine and lysine are both hydrophilic amino acids. Asparagine-to-lysine substitutions have been shown to affect the conformation and binding affinity of proteins [81,82]. Nevertheless, the candidate genes discussed in this study should be examined separately to accurately assess their effect on FT and to determine whether the specific alleles found in this panel of Nordic cultivars and landraces could be introgressed into new climate-resilient varieties of winter wheat.…”

Section: Snps Associated With Overwintering In the Fieldmentioning

confidence: 99%

Genome-Wide Association Analysis of Freezing Tolerance and Winter Hardiness in Winter Wheat of Nordic Origin

Vaitkevičiūtė,

Chawade,

Lillemo

et al. 2023

Plants

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Climate change and global food security efforts are driving the need for adaptable crops in higher latitude temperate regions. To achieve this, traits linked with winter hardiness must be introduced in winter-type crops. Here, we evaluated the freezing tolerance (FT) of a panel of 160 winter wheat genotypes of Nordic origin under controlled conditions and compared the data with the winter hardiness of 74 of these genotypes from a total of five field trials at two locations in Norway. Germplasm with high FT was identified, and significant differences in FT were detected based on country of origin, release years, and culton type. FT measurements under controlled conditions significantly correlated with overwintering survival scores in the field (r ≤ 0.61) and were shown to be a reliable complementary high-throughput method for FT evaluation. Genome-wide association studies (GWAS) revealed five single nucleotide polymorphism (SNP) markers associated with FT under controlled conditions mapped to chromosomes 2A, 2B, 5A, 5B, and 7A. Field trials yielded 11 significant SNP markers located within or near genes, mapped to chromosomes 2B, 3B, 4A, 5B, 6B, and 7D. Candidate genes identified in this study can be introduced into the breeding programs of winter wheat in the Nordic region.

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Influence of an asparagine to lysine mutation at amino acid 3516 of apolipoprotein B on low-density lipoprotein receptor binding

Cited by 12 publications

References 31 publications

Novel mutations of thePCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia

Novel mutations of thePCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia

Genetic heterogeneity of autosomal dominant hypercholesterolemia

Genome-Wide Association Analysis of Freezing Tolerance and Winter Hardiness in Winter Wheat of Nordic Origin

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