APOA1 – AApoAI amyloidosis

Apolipoprotein A-I (APOA1) variants cause autosomal dominant AApoAI amyloidosis. To date, 3 unrelated probands have been reported with heterozygous amyloidogenic substitutions presenting with organ‐restricted amyloid: Leu75Pro in hepatic amyloidosis (PMID:14986480), Leu64Pro in renal amyloidosis (PMID:15558533), and Trp74Arg in glomerular deposition with nephrotic syndrome (PMID:27240838). No multi‐generation segregation data are available, and penetrance appears variable with asymptomatic carriers identified.

Biochemical extraction and characterization of patient‐derived fibrils consistently demonstrate deposition of an N-terminal ~96-residue fragment of ApoA-I containing the pathogenic substitution, supporting a misfolding‐driven (gain-of-function) mechanism. Overall clinical validity is Limited given 3 probands and absent segregation; functional evidence is also Limited but concordant with tissue pathology. APOA1 variant screening should be considered in patients with unexplained hepatic or renal amyloidosis to guide diagnosis and genetic counselling.

References

• Amyloid: the international journal of experimental and clinical investigation • 2003 • Hepatic amyloidosis resulting from deposition of the apolipoprotein A-I variant Leu75Pro. PMID:14986480
• American journal of kidney diseases • 2004 • Renal apolipoprotein A-I amyloidosis associated with a novel mutant Leu64Pro. PMID:15558533
• European journal of medical genetics • 2016 • A case report of hereditary apolipoprotein A-I amyloidosis associated with a novel APOA1 mutation and variable phenotype. PMID:27240838

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