A novel type of familial hypercholesterolemia: Double heterozygous mutations in LDL receptor and LDL receptor adaptor protein 1 gene

Abstract

Background: Autosomal recessive hypercholesterolemia (ARH) is an extremely rare inherited hypercholesterolemia, the cause of which is mutations in low-density lipoprotein (LDL) receptor adaptor protein 1 (LDLRAP1) gene. Methods:A total of 146 heterozygous familial hypercholesterolemic (FH) patients with a mutation in LDLR gene were screened for genes encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and LDLRAP1.Results: Among the 146 subjects, we identified a 79-year-old Japanese female with double mutations in LDLR gene (c.2431A>T) and LDLRAP1 gene (c.606dup). Two other relatives with double mutations in those genes in her family were also identified. Although the proband exhibited massive Achilles tendon xanthoma and coronary and aortic valvular disease, serum LDL-C level of subjects with double mutations was similar with that of subjects with single LDLR mutation (284.0±43.5 versus 265.1±57.4mg/dl). Conclusion:Additional mutation in LDLRAP1 may account for severer phenotype in terms of xanthoma and atherosclerotic cardiovascular disease in FH patients. 2

Half a Century Tales of Familial Hypercholesterolemia (FH) in Japan

“…FH caused by autosomal recessive hypercholesterolemia (ARH) 13, 14) and signal-transducing adaptor family member 1 abnormality 15) has also been reported. Similarly, the discovery of several other genes causing FH is anticipated.…”

Management of Familial Hypercholesterolemia: A Review of the Recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia

“…17 The LDLRAP1 gene encodes an adaptor protein for trafficking of LDL receptors in cells in the liver, and mutations have been identified in patients with either FH, an autosomal dominant disorder, or an autosomal recessive hypercholesterolemia. 18,19 Elevations in LDL-C levels are a function of the severity of the genetic mutation and whether it is homozygous or compound heterozygous. 1 When left untreated, patients with HeFH typically have 2-to 3-fold higher levels of plasma LDL-C compared with healthy individual (about 200-400 mg/dL), whereas patients with HoFH have levels of LDL-C that are 6-to 10-fold higher than normal (> 600 mg/dL).…”

Cascade Screening for Familial Hypercholesterolemia: PCR Methods with Melting-Curve Genotyping for the Targeted Molecular Detection of Apolipoprotein B and LDL Receptor Gene Mutations to Identify Affected Relatives

“…More than 80% of FH patients have mutations in the LDL receptor (LDLR), 6 which leads to defective uptake or processing of LDL particles (4). Disease-causing mutations have also been identified in apolipoprotein B (APOB) and in proprotein convertase subtilisin/kexin type 9 (PCSK9) genes; these comprise around 5% and 2% of all UK FH mutations, respectively (5).…”

“…Disease-causing mutations have also been identified in apolipoprotein B (APOB) and in proprotein convertase subtilisin/kexin type 9 (PCSK9) genes; these comprise around 5% and 2% of all UK FH mutations, respectively (5). Mutations have also been identified in the LDL receptor adaptor protein 1 (LDLRAP1) gene, seen in a recessive form of FH (6). Despite their greatly increased risk of coronary heart disease, most individuals with FH remain undiagnosed, untreated, or inadequately treated.…”