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De Castro-Orós et al

FH characterized by null allele mutations of LDLR show a more severe clinical phenotype and worse advanced carotid artherosclerosis than those with receptor-defective muta- tions, independently of age, gender, lipid, and nonlipid risk factor.76

Other genes associated with FH Apolipoprotein B

In 1986, Vega and Grundy77 showed that some patients (5 of 15 studied) with hypercholesterolemia have reduced clearance of LDL not because of decreased activity of LDLr but because of a defect in structure or composition of LDL that reduces its affinity for receptors. Innerarity et al78 found that moderate hypercholesterolemia, presented in the five subjects previously studied, could be attributed to a defective receptor binding of a genetically altered Apo B-100 to the LDLr.77,78 The inherited nature of this disease was indicated by the findings of the same defect in proband’s first-degree relatives. These findings resulted in referring this disease as Familial Defective Apo B-100 (FDB).78

The first mutation found as a FDB cause was demonstrated by Soria et al79 who sequenced the two alleles of APOB from patients of three families. They observed the mutation R3500Q.79 Two new mutations were described in 1995 as cause of FDB: R3500W and R3531C.80,81 For the classical mutation, R3500Q, frequency was estimated in 1:500–1:700 in several Caucasian populations in North America and Europe (Table 1).82 On the other hand, R3500W and R3531C have been found in a minor frequency.

Recently, a novel mutation H3543Y in APOB associated with FDB has been described with a high prevalence (4 times R3500Q) in a German population.83

Recent data reveal that compared with FH patients with LDLR mutations, FDB patients have lower LDLc levels by 20%–25% (Table 3),84 respond better to statins and have lower risk of CHD.85 This difference could be due to normal clearance of very low-density lipoprotein remnants through Apo E-mediated uptake in FDB.86

Proprotein convertase subtilisin/kexin type 9 gene

In 1999, Varret et al87 identify a new autosomal dominant hypercholesterolemia (ADH) locus in 1q34.1-p32 chromo- some (Tables 1 and 2). PCSK9 was first identified as a mem- ber of proprotein convertase family with hepatic, intestine, and kidney expression.88 Mutations in PCSK9 gene (S127R, P216L, and D374Y y N157K) that produce gain of function were associated with a decrease in LDLr number andADH.89


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Initially, it was thought the hypothesis of a PCSK9 role in LDLr degradation in the cell surface.89 Nowadays, as we have described earlier, there are enough evidence to think that PCSK9 participates in LDLr lysosomal degradation (Figure 1).39,40,90 Recently, it has been proposed that PCSK9 may induce internalization and degradation of LDLr by leading receptor to ubiquitination by Idol.91

PCSK9 mutations have been also classified into five classes, including “null alleles”, mutations that affect autocatalytic scission avoiding the protein transport through endoplasmic reticulum or from the endoplasmic reticulum to cell surface, alleles that affects PCSK9 stability and finally mutations that produce gain of function because of gene overexpression.92–94 Some mutations in PCSK9 (Y142X, C679X, and R46L) produce a loss of function and are associated with low LDLc.95,96

About 17%–33% of patients with a clinical diagnosis of monogenic hypercholesterolemia based on Simon Broome Register Group (SBRG) criteria do not harbor any genetic cause in the known loci suggesting a possibility of additional hypercholesterolemia loci (Table 1).9,10

FH diagnosis

Clinical criteria used to identify patients with FH include high plasma levels of total and LDLc (.250 mg/dL or .7 mmol/L), family history of hypercholesterolemia especially in children, deposition of cholesterol in extravas- cular tissues such as TX or corneal arcus, and personal and family history of premature CVD.1 Heterozygous FH (heFH) patients have LDLc levels approximately twice those of the normal population, ranging from 190 to 400 mg/dL (4.9–10.3 mmol/L). Triglycerides (TG) levels are usually in the normal range. However, some patients with FH have increased TG levels, explained in part by the interaction with other genes (ie, E2/E2 genotype) or environmental factors (ie, alcohol, overweight, and diabetes mellitus).

TX are pathognomonic of FH; however, their identification is not always easy and they are considered insensitive diagnos- tic markers. A high variability of xanthoma presence in FH patients has been reported.97 Xanthelasmas occur commonly in heterozygotes, but are rare in homozygotes. Xanthelasmas are not specific for FH and can appear in subjects with normal lipid levels.1 TX may appear in patients with cerebrotendinous xanthomatosis and are indistinguishable from those FH. This kind of xanthomas also occur in subjects affected by FDB, dysbetalipoproteinemia, and sitosterolemia (Table 3).1

Variability in the frequency observed in different studies depends in part on the clinical criteria used for FH (some of

The Application of Clinical Genetics 2010:3

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