Experiences with the Homozygous Cases of Familial Hypercholesterolemia

Khachadurian, Avedis K.; Uthman, S

doi:10.1159/000175431

Cited by 173 publications

(54 citation statements)

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“…Familial hypercholesterolemia is particularly common in Lebanon (Khachadurian et al 1973;Lehrman et al 1987). The p.Cys681X mutation was first identified by Lehrman and collaborators in three homozygous unrelated Lebanese patients (1987).…”

Section: Discussionmentioning

confidence: 99%

“…Detection of heterozygotes is crucial in the Lebanese population where the high prevalence of heterozygosity of FH among Lebanese people, coupled with a high incidence of consanguinity increases over 10-fold the proportion of homozygotes (Khachadurian et al 1973). The evaluation of the incidence of the p.Cys681X mutation in Lebanon, the confirmation of its major impact and the detection of new mutations are very helpful in establishing a rapid and early screening method for FH genetic diagnosis in Lebanon and in FH families of Lebanese origin around the world, in order to prevent cardiovascular complications in probands and their relatives carrying the mutation.…”

Section: Discussionmentioning

confidence: 99%

“…In Lebanon, the frequency of the homozygous condition is more than 10-fold higher than in other populations. This is attributable to a high prevalence of heterozygosity of FH among Lebanese people, coupled with a high incidence of consanguinity which increases the proportion of homozygotes (Lehrman et al 1987;Khachadurian et al 1973). Lehrman and co-workers identified in 1987 a mutation in the LDLR gene responsible for FH in 3 Lebanese and 1 Syrian homozygous probands.…”

Section: Genetic Of Familial Hypercholesterolemia In Lebanonmentioning

confidence: 99%

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The molecular basis of familial hypercholesterolemia in Lebanon: Spectrum ofLDLRmutations and role ofPCSK9as a modifier gene

et al. 2009

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ABSTRACT:Autosomal dominant hypercholesterolemia (ADH), a major risk for coronary heart disease, is associated with mutations in the genes encoding the low-density lipoproteins receptor (LDLR), its ligand apolipoprotein B (APOB) or PCSK9 (Proprotein Convertase Subtilin Kexin 9). Familial hypercholesterolemia (FH) caused by mutation in the LDLR gene is the most frequent form of ADH. The incidence of FH is particularly high in the Lebanese population presumably as a result of a founder effect. In this study we characterize the spectrum of the mutations causing FH in Lebanon: we confirm the very high frequency of the LDLR p.Cys681X mutation that accounts for 81.5 % of the FH Lebanese probands recruited and identify other less frequent mutations in the LDLR. Finally, we show that the p.Leu21dup, an in frame insertion of one leucine to the stretch of 9 leucines in exon 1 of PCSK9, known to be associated with lower LDL-cholesterol levels in general populations, is also associated with a reduction of LDL-cholesterol levels in FH patients sharing the p.C681X mutation in the LDLR. Thus, by studying for the first time the impact of PCSK9 polymorphism on LDL-cholesterol levels of FH patients carrying a same LDLR mutation, we show that PCSK9 might constitute a modifier gene in familial hypercholesterolemia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Genetic Of Familial Hypercholesterolemia In Lebanonmentioning

confidence: 99%

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The molecular basis of familial hypercholesterolemia in Lebanon: Spectrum ofLDLRmutations and role ofPCSK9as a modifier gene

et al. 2009

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“…Hobbs). Twelve of these samples were from probands with presumed autosomal recessive hypercholesterolemia, who had marked elevations in plasma cholesterol, tendon xanthomas, and normolipidemic parents (Khachadurian and Uthman 1973;Sirtori et al 1991;Zuliani et al 1995). In addition, subjects with each of the following disorders were analyzed: (1) severe hypercholesterolemia (∼2000 mg/dL), bony lesions, and liver disease of unknown etiology (n = 1); (2) hypolipidemia (cholesterol level of 100 mg/dL, triglyceride level of 45 mg/dL), and xanthomatosis (n = 1); (3) type III hyperlipidemia that does not cosegregate with apoE (Giroux et al 1997) or that has an atypical lipoprotein profile (n = 7); (4) nonalcoholic steatohepatitis (n = 1); (5) FH that does not respond to HMG-CoA reductase inhibitors (n = 1); (6) congenital generalized lipodystrophy (n = 1); and (7) multiple symmetric lipomatosis (n = 1; Enzi 1984).…”

Section: Methods Subjectsmentioning

confidence: 99%

Sequence Diversity in Genes of Lipid Metabolism

Garcia¹,

Mues

Liao

et al. 2001

Genome Res.

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Elevated plasma lipoprotein levels play a crucial role in the development of coronary artery disease. Genetic factors strongly influence the levels of plasma lipoproteins, but the genes and sequence variations contributing to the most common forms of dyslipidemias are not known. We used GeneChip probe arrays to resequence the coding regions of 10 key genes of lipid metabolism. The sequences of these genes were analyzed in 80 dyslipidemic individuals. Fourteen nonsynonymous and twenty-two synonymous single nucleotide changes were identified that could be confirmed by conventional sequencing. Seven of the fourteen nonsynonymous sequence variants were polymorphisms with allele frequency >1% in the general population. The remaining seven were not found in normolipidemic controls (25 Caucasians and 25 African-Americans). The relationship between nonsynonymous sequence variations and various dyslipidemias was explored in association and family studies. No evidence was found for coding sequence variations in any of the 10 genes contributing to dyslipidemia. Only a single sequence variation, a missense mutation in the low density lipoprotein receptor gene, co-segregated with hyperlipidemia in the proband's family. This study illustrates some of the difficulties associated with identifying sequence variations contributing to complex traits.

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“…The first significant clue came a decade later from studies of patients with autosomal recessive hypercholesterolemia (ARH), who were described as clinically similar to FH patients but carried no LDLR mutations (8). The genetic defects in ARH patients were mapped to a single gene that codes for a 308-amino acids protein, named ARH, which was required for the function of LDLR in hepatocytes (9).…”

mentioning

confidence: 99%

Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail

Dvir

Shah

Gottardi

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Hypercholesterolemia, high serum cholesterol in the form of LDL, is a major risk factor for atherosclerosis. LDL is mostly degraded in the liver after its cellular internalization with the LDL receptor (LDLR). This clathrin-mediated endocytosis depends on the protein autosomal recessive hypercholesterolemia (ARH), which binds the LDLR cytoplasmic tail. Mutations in either the LDLR tail or in ARH lead to hypercholesterolemia and premature atherosclerosis. Despite the significance of this interaction for cholesterol homeostasis, no structure of either ARH or the LDLR tail is available to determine its molecular basis. We report the crystal structure at 1.37-Å resolution of the phosphotyrosine-binding (PTB) domain of ARH in complex with an LDLR tail peptide containing the FxNPxY 0 internalization signal. Surprisingly, ARH interacts with a longer portion of the tail than previously recognized, which extends to I -7 xF -5 xNPxY 0 QK +2 . The LDLR tail assumes a unique "Hook"-like structure with a double β-turn conformation, which is accommodated in distinctive ARH structural determinants (i.e., an extended backbone hydrogen-bonding platform, three hydrophobic helical grooves, and a hydrophobic pocket for Y 0 ). This unique complementarity differs significantly in related PTB proteins and may account for the unique physiological role of these partners in the hepatic uptake of cholesterol LDL. Moreover, the unusual hydrophobic pocket for Y 0 explains the distinctive ability of ARH to internalize proteins containing either FxNPxY 0 or FxNPxF 0 sequences. Biophysical measurements reveal how mutations associated with hypercholesterolemia destabilize ARH and its complex with LDLR and illuminate LDL internalization defects seen in patients.lipoprotein | crystallography | trafficking | lipid metabolism

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Experiences with the Homozygous Cases of Familial Hypercholesterolemia

Cited by 173 publications

References 5 publications

The molecular basis of familial hypercholesterolemia in Lebanon: Spectrum ofLDLRmutations and role ofPCSK9as a modifier gene

The molecular basis of familial hypercholesterolemia in Lebanon: Spectrum ofLDLRmutations and role ofPCSK9as a modifier gene

Sequence Diversity in Genes of Lipid Metabolism

Atomic structure of the autosomal recessive hypercholesterolemia phosphotyrosine-binding domain in complex with the LDL-receptor tail

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