A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy.

Area of Science:

• Genetics
• Nephrology
• Biochemistry

Background:

• Lipoprotein glomerulopathy (LPG) is a kidney disease characterized by lipoprotein thrombosis within glomeruli and elevated plasma apolipoprotein (apo) E levels.
• A previously identified apo E variant, apo E2 (Arg145Pro) Sendai, has been associated with LPG in some patients.
• This study investigates a novel apo E gene mutation in an LPG patient.

Purpose of the Study:

• To identify and characterize a novel apolipoprotein E (apo E) mutation in a patient with lipoprotein glomerulopathy (LPG).
• To investigate the functional consequences of this novel apo E variant on low-density lipoprotein (LDL) receptor binding.

Main Methods:

• Genomic DNA sequencing and restriction fragment length polymorphism (RFLP) were used to detect and confirm the mutation.
• Recombinant proteins of the mutant apo E2 (Arg25Cys) Kyoto and normal apo E3 were expressed in COS-1 cells.
• In vitro competition assays were performed to determine the LDL receptor-binding activities of the apo E variants.

Main Results:

• A novel C to T transition was identified, resulting in an arginine to cysteine substitution at residue 25 of apo E (apo E2 (Arg25Cys) Kyoto).
• The propositus was a heterozygous carrier of apo E2 (Arg25Cys) Kyoto. His mother carried the mutation and had dysbetalipoproteinemia but not LPG.
• Recombinant apo E2 (Arg25Cys) Kyoto exhibited significantly reduced LDL receptor-binding activity, displacing only 10% of LDL compared to normal apo E3.

Conclusions:

• Apo E2 (Arg25Cys) Kyoto is a novel mutation causally linked to lipoprotein glomerulopathy (LPG).
• The development of LPG likely involves additional genetic or environmental factors beyond this specific apo E mutation.
• Arginine-25 of apo E is crucial for its receptor-binding function, as demonstrated by the impaired binding of the mutant variant.