Pathologic
amyloid accumulates in the CNS or in peripheral organs, yet the mechanism underlying the targeting of systemic
amyloid deposits is unclear.
Serum amyloid A (SAA) 1 and 2 are produced predominantly by the liver and form
amyloid most commonly in the spleen, liver, and kidney. In contrast, SAA3 is produced primarily extrahepatically and has no causal link to
amyloid formation. Here, we identified 8
amyloidosis cases with
amyloid composed of SAA3 expanding the uterine wall of goats with near-term fetuses. Uterine
amyloid accumulated in the endometrium, only at the site of placental attachment, compromising maternal-fetal gas and nutrient exchange and leading to fetal
ischemia and death. No other organ contained
amyloid. SAA3
mRNA levels in the uterine endometrium were as high as SAA2 in the liver, yet mass spectrometry of the insoluble uterine
peptides identified SAA3 as the predominant
protein, and not SAA1 or SAA2. These findings suggest that high local SAA3 production led to deposition at this unusual site. Although
amyloid A (AA)
amyloid deposits typically consist of an N-terminal fragment of SAA1 or SAA2, here, abundant C-terminal
peptides indicated that the uterine
amyloid was largely composed of full-length SAA3. The exclusive deposition of SAA3
amyloid in the uterus, together with elevated uterine SAA3 transcripts, suggests that the uterine
amyloid deposits were due to locally produced SAA3. This is the first report of SAA3 as a cause of
amyloidosis and of AA
amyloid deposited exclusively in the uterus.