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Eight novel LDL receptor gene mutations among patients under LDL apheresis in Dresden and Leipzig
H Bochmann1, J Geisel, W Herrmann
1Technical University Dresden, Medical Faculty, Institute of Clinical Chemistry and Laboratory Medicine, Fetscherstrasse 74, 01307 Dresden, Germany.
Insights
Genetic screening of LDL apheresis patients revealed LDL receptor gene mutations in 61% of individuals with severe hypercholesterolemia. This highlights the importance of DNA analysis for early diagnosis and treatment of high-risk patients.
Area of Science:
- Medical Genetics
- Cardiovascular Disease Research
- Biochemistry
Background:
- LDL apheresis effectively lowers high cholesterol but is reserved for severe, refractory cases.
- Mutations in the LDL receptor (LDL-R) gene are primary genetic causes of severe hypercholesterolemia.
- Understanding the genetic basis in apheresis patients can improve diagnosis and treatment.
Purpose of the Study:
- To screen the LDL-R gene in LDL apheresis patients from Saxony.
- To determine if specific mutations are frequent causes of their atherogenic hypercholesterolemia.
- To assess the utility of DNA analysis in identifying high-risk individuals.
Main Methods:
- Screening of the LDL-R gene in 31 unrelated patients using SSCP and/or automated sequencing.
- Genotyping for the familial defective apolipoprotein B-100 (FDB) mutation via PCR.
- Analysis of mutation types including missense, nonsense, insertions, and deletions.
Main Results:
- Nineteen of 31 patients (approximately 61%) carried an LDL-R mutation.
- Ten novel mutations were identified, alongside previously known mutations.
- Two patients were heterozygous for the FDB mutation; one patient was compound heterozygous for two missense mutations.
Conclusions:
- A genetic cause related to the LDL-R gene was identified in a significant majority of severe hypercholesterolemia patients undergoing LDL apheresis.
- DNA analysis is crucial for early identification and targeted treatment of individuals with genetic hypercholesterolemia.
- This study establishes a genetic basis for hypercholesterolemia in a substantial portion of the examined patient cohort.
Abstract:
LDL apheresis is highly efficient in reducing elevated plasma cholesterol. Due to strict indications only patients with severe, refractory hypercholesterolemia are treated with this method. Mutations in the LDL receptor gene are major genetic causes for severe hypercholesterolemia. Screening the entire gene in LDL apheresis patients from Saxony should determine whether an increased frequency of defined mutations is responsible for the atherogenic hypercholesterolemia in this group. 31 unrelated patients (15 male, 16 female, age 33-71 yrs.) were included in the analysis. The LDL-R gene was screened using SSCP and/or automated sequencing. The familial defective apolipoprotein B-100 (FDB) mutation was genotyped using established PCR techniques. Nineteen of 31 patients were carriers of an LDL-R mutation. Ten missense and two nonsense mutations, three insertions and two deletions were detected. The mutations C74S, C74R, T87M, 660delC, 662insCCCCG, 680insGGACAAATCTGA, 1428insC and 2167delG have not been previously described. One patient was compound heterozygous for two missense mutations. Two further patients were heterozygous for FDB. No mutations were found among controls. A genetic background for hypercholesterolemia in the LDL-R could be established in about 61% of the patients examined. Therefore, methods of DNA analysis allow to recognize and adequately treat a large portion of high-risk individuals at an early stage.
