Variant apolipoprotein AI as a major constituent of a human hereditary amyloid

Area of Science:

• Biochemistry
• Genetics
• Neurology

Background:

• Familial Amyloidotic Polyneuropathy (FAP) is a group of rare, autosomal dominant hereditary disorders.
• Amyloidosis involves the abnormal deposition of proteins, forming fibrils that can damage organs.
• Type III (Iowa) FAP is a specific subtype characterized by neurological and systemic symptoms.

Purpose of the Study:

• To identify the major protein constituent of amyloid fibrils in a patient with Familial Amyloidotic Polyneuropathy Type III (Iowa).
• To characterize the specific mutation responsible for amyloid formation in this case.
• To establish the role of apolipoprotein AI in this form of hereditary amyloidosis.

Main Methods:

• Isolation of amyloid fibrils from patient spleen and liver tissues.
• Protein sequencing and analysis to determine the amino acid composition and identify the N-terminal sequence.
• Mutation analysis to pinpoint specific amino acid substitutions.

Main Results:

• Amyloid fibrils were successfully isolated from the spleen and liver.
• The primary protein component was identified as the amino-terminal portion (residues 1-83) of apolipoprotein AI.
• A specific mutation, arginine for glycine substitution at position 26 (R26G), was identified in apolipoprotein AI.
• This represents the first documented case of apolipoprotein AI as a major amyloid constituent in human autosomal dominant hereditary amyloidosis.

Conclusions:

• Apolipoprotein AI, specifically with the R26G mutation, is the major constituent of amyloid fibrils in this patient with FAP Type III (Iowa).
• This finding expands the known spectrum of proteins implicated in hereditary amyloidosis.
• The study highlights the potential role of apolipoproteins in the pathogenesis of certain forms of amyloid disease.