Two families with hereditary renal amyloidosis were found to have a novel mutation in the fibrinogen Aα chain gene. This form of amyloidosis is an autosomal dominant condition characterized by proteinuria, hypertension, and subsequent azotemia. DNAs of patients with amyloidosis were screened for a polymorphism in fibrinogen Aα chain gene by single-strand conformation polymorphism analysis, and affected individuals from two kindreds were found to have a mutation. Both of these kindreds are American of Irish descent presenting with non-neuropathic, nephropathic amyloidosis in the fifth to the seventh decade of life. DNA sequencing showed a point mutation in the fibrinogen Aα chain gene that is responsible for substitution of valine for glutamic acid at position 526. By restriction fragment length polymorphism analysis, 7 affected individuals and 14 asymptomatic individuals in these two kindreds were positive for the fibrinogen Aα chain Val 526 gene. Fibrinogen was isolated from plasma of a heterozygous gene carrier and shown to contain ~ 50% variant fibrinogen. Discovery of this new mutation confirms the association between fibrinogen Aα chain variant and hereditary renal amyloidosis and establishes a new biochemical subtype of amyloidosis.
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