Linda Makatini said in a statement that Vusi Nhlakanipho Zuma had died on Sunday after complications from the disease, which can cause chronic inflammation.
Systemic lupus erythematosus (SLE) affects many parts of the body, including the skin, joints and internal organs.
Lots of people can have the condition for a long time without knowing before they get a sudden flare-up.
The symptoms include extreme tiredness, rashes (especially on the face, wrists and hands) and joint pain and swelling.
Vusi Nhlakanipho was the youngest son of Mr Zuma and his late wife Kate Mantsho and Mr Zuma is so distraught over the passing of his son.
His funeral is expected take place on Saturday in Johannesburg.