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A 34-year-old man is found to have an LDL level of 310 mg/dL and a normal serum triglyceride level.  His father suffered a myocardial infarction at age 39, and his paternal grandfather died of a heart attack at age 40.  The patient's wife has a normal lipid profile.  DNA samples are obtained from several family members for genetic analysis.  Southern blotting of restriction fragments from a region containing the LDL receptor gene shows the following pattern:

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Which of the following statements best describes the DNA analysis results?

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Explanation:

This patient most likely has heterozygous familial hypercholesterolemia, an autosomal dominant LDL receptor defect that causes high LDL levels and increases the risk of premature atherosclerosis.  Homozygous familial hypercholesterolemia (a rarer and more severe form of the disease due to inheritance of 2 defective LDL receptor alleles) often presents with coronary heart disease in childhood/adolescence.

Southern blotting is a technique that can be used to detect DNA mutations.  The process involves the following steps:

  1. DNA extraction from the individual's cells
  2. Restriction endonuclease digestion of the DNA sample into fragments
  3. Gel electrophoresis to separate the various sizes of DNA fragments; larger fragments move slowly and shorter fragments move faster
  4. DNA probe (a single-stranded segment of labeled DNA complementary to the gene of interest) to identify the target gene

Once the gene of interest is identified by the DNA probe, various family members' Southern blots can be compared.  Because both the patient and his father are affected, the common DNA segment between them (8 kb segment) most likely represents the mutated gene.  The patient's son also has the 8 kb segment, meaning that he is probably affected as well.

(Choice A)  Familial hypercholesterolemia is an autosomal dominant disorder.  X-linked recessive mutations are transmitted from unaffected carrier mothers to their sons.  Father-to-son transmission does not occur.

(Choices B and D)  The patient (affected by the disease) does not possess the 10 kb segment, so this segment does not correspond to the mutated gene.  The patient's brother inherited the 10 kb segment from his father (not the 8kb mutated segment), so he would not be affected.

(Choice C)  The patient and his brother, but not their father, have a 12 kb segment on Southern blot analysis.  Therefore, this segment was likely inherited from the mother and does not carry the mutation.

Educational objective:
Southern blotting is a technique used to identify DNA mutations.  It involves restriction endonuclease digestion of sample DNA, gel electrophoresis, and gene identification with a labeled DNA probe.