HEREDITARY RENAL AMYLOIDOSIS WITH A NOVEL VARIANT FIBRINOGEN

Two families with hereditary renal amyloidosis were found to have a no vel mutation in the fibrinogen A alpha chain gene. This form of amyloi dosis is an autosomal dominant condition characterized by proteinuria, hypertension, and subsequent azotemia. DNAs of patients with amyloido sis were screened for a polymorphism in fibrinogen A alpha chain gene by single-strand conformation polymorphism analysis, and affected indi viduals from two kindreds were found to have a mutation. Both of these kindreds are American of Irish descent presenting with nonneuropathic , nephropathic amyloidosis in the fifth to the seventh decade of life. DNA sequencing showed a point mutation in the fibrinogen A alpha chai n gene that is responsible for substitution of valine for glutamic aci d at position 526. By restriction fragment length polymorphism analysi s, 7 affected individuals and 14 asymptomatic individuals in these two kindreds were positive for the fibrinogen A alpha chain Val 526 gene. Fibrinogen was isolated from plasma of a heterozygous gene carrier an d shown to contain similar to 50% variant fibrinogen. Discovery of thi s new mutation confirms the association between fibrinogen A alpha cha in variant and hereditary renal amyloidosis and establishes a new bioc hemical subtype of amyloidosis.