Alternative titles; symbolsHYPERCHOLESTEROLEMIA, AUTOSOMAL DOMINANT, 3; HCHOLA3FH3Other entities represented in this entry:LOW DENSITY LIPOPROTEIN CHOLESTEROL LE...
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Familial hypercholesterolemia-3 (FHCL3) is an autosomal dominant disorder of lipid metabolism characterized by a selective increase of low density lipoprotein particles in plasma, giving rise to tendon and skin xanthomas, arcus corneae, and coronary artery disease (summary by Varret et al., 1999).
For a general description and a discussion of genetic heterogeneity of hypercholesterolemia, see 143890.
Varret et al. (1999) reported a large 3-generation French family (HC2) in which 7 individuals had hypercholesterolemia. All affected members had levels of total cholesterol above the 97th percentile when compared with age- and sex-matched French individuals. The proband was a 36-year-old woman, ascertained at age 17 years with 3.32 g/l total cholesterol, 2.36 g/l LDL-C, 0.48 g/l HDL-C, 0.61 g/l triglycerides, and arcus corneae. Her sister, aged 40 years, was ascertained at age 20 years with similar lipid levels, arcus corneae, tendon xanthomas, and xanthelasmas.
Haddad et al. (1999) reported a large Utah kindred (K1173) segregating hypercholesterolemia. In this pedigree, the LDL levels (mean, 237 +/-70) were similar to those of familial hypercholesterolemia pedigrees with mutations in the LDL receptor gene (FHCL1; 606945), and penetrance was complete even at young ages. Triglyceride levels were significantly lower than in FHCL1 pedigrees, but mean age and body mass index were also lower. There were no differences in the frequency of tendon xanthomas or coronary artery disease.
The transmission pattern of hyercholesterolemia in the French family reported by Varret et al. (1999) was consistent with autosomal dominant inheritance.
Varret et al. (1999) identified a large French pedigree and 12 additional Caucasian families with autosomal dominant hypercholesterolemia in which linkage to both the LDLR gene (606945) and the APOB gene (107730) was excluded, implicating a new locus, which they designated FH3. A lod score of 3.13 at a recombination fraction of 0.0 was obtained at markers D1S2892 and D1S2722. Varret et al. (1999) localized the FH3 locus to a 9-cM interval at 1p34.1-p32. Heterogeneity tests indicated linkage to FH3 in approximately 27% of these non-LDLR/non-APOB autosomal dominant hypercholesterolemia families, implying the existence of yet a fourth locus.
Hunt et al. (2000) found that familial hypercholesterolemia in a Utah kindred (K1173), previously described by Haddad et al. (1999), mapped to 1p32. Hunt et al. (2000) mapped the disorder to a region of approximately 17 cM between markers D1S2130 and D1S1596. This region appeared to overlap the region found to be linked to severe hypercholesterolemia in French and Spanish families by Varret et al. (1999). By expansion of the K1173 pedigree and increased marker density within the region of interest, Timms et al. (2004) narrowed the linked region. They also identified additional families sharing the same microsatellite haplotype. Whereas all haplotype carriers in the K1173 kindred were affected, the haplotype carriers within the newly identified families were unaffected, suggesting that the causal mutation had occurred after divergence of these pedigrees from a common ancestor.
▼ Molecular Genetics
Abifadel et al. (2003) carried out positional cloning using the French family (HC92) in which linkage was originally identified by Varret et al. (1999) and 23 French families in which involvement of LDLR (606945) and APOB (107730) had been excluded as the site of causative mutations. The critical region was found to contain 41 genes, including PCSK9 (607786). They identified PCSK9 mutations (607786.0001 and 607786.0002) in 3 French families with hypercholesterolemia.
By mutation screening of genes in the chromosome 1p32 region in patients with familial hypercholesterolemia from the Utah pedigree (K1173) studied by Haddad et al. (1999) and Hunt et al. (2000), Timms et al. (2004) identified a D374Y (607786.0003) mutation in the PCSK9 gene.
In 3 of 64 African American subjects with low plasma levels of low density lipoprotein cholesterol (LDLCQ1), Cohen et al. (2005) identified a nonsense mutation (Y142X; 607786.0004) in the PCSK9 gene.