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Published on: September 15, 2018
Japanese familial hypercholesterolaemia with a 327insC mutation in the LDL receptor gene
Ryoji Hirota1, Nobuhiko Kubo, Kazumasa Hikiji
1Department of Clinical Pathology, Omiya Medical Center, Jichi Medical School, Saitama Prefecture 330-8503, Japan.
Insights
A novel mutation in the LDL receptor (LDLR) gene causes familial hypercholesterolaemia (FH). This FH patient had high cholesterol but no heart disease, suggesting LDLR mutations may not always lead to severe outcomes.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Molecular Biology
Background:
- Familial hypercholesterolaemia (FH) is an autosomal dominant genetic disorder.
- Mutations in the LDL receptor (LDLR) gene are a primary cause of FH.
- FH typically leads to premature coronary atherosclerosis and cardiovascular disease.
Observation:
- A 59-year-old male patient with FH presented with severe hypercholesterolaemia (12.2 mmol/L at age 44).
- He carried a novel heterozygous frameshift mutation (327insC) in exon 4 of the LDLR gene, creating a premature termination codon.
- Despite over 20 years of lipid-lowering therapy, his total cholesterol remained elevated (above 7.8 mmol/L).
Findings:
- The patient and his family members with the LDLR mutation did not develop ischaemic heart disease or xanthoma.
- The mutation 327insC was identified in an intensive survey of Japanese FH patients, indicating a potentially low incidence in the Kanto area.
Implications:
- This case highlights that certain LDLR mutations may not invariably result in severe cardiovascular complications.
- Understanding genotype-phenotype correlations in FH is crucial for accurate risk assessment.
- Further research is needed to explore the mechanisms underlying the attenuated phenotype in patients with this specific LDLR mutation.
Abstract:
Mutations in the LDL receptor (LDLR) cause familial hypercholesterolaemia (FH) in an autosomal dominant manner. The condition frequently progresses to coronary atherosclerosis. We describe a patient with FH, but without ischaemic heart disease, who had a novel frameshift mutation (327insC) in exon 4 of the LDLR gene. This mutation introduced a premature termination codon (TGA, codon 158). The patient was a 59-year-old man who had presented with hypercholesterolaemia and a plasma total cholesterol (TC) concentration of 12.2 mmol/L at age 44 years. The mutation 327insC in this patient was heterozygous and hypercholesterolaemia was common within his family. Despite taking lipid-lowering medications (probucol and pravastatin) for more than 20 years, his TC concentration hardly fell below 7.8 mmol/L. However, neither the patient nor anyone else in his family developed characteristic symptoms of ischaemic heart disease or xanthoma. This patient was discovered by an intensive mutation survey among 22 unrelated Japanese with FH mainly in the Kanto area of Japan, suggesting a low incidence of the mutation in the area.
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