AA amyloidosis associated with a mutated serum amyloid A4 protein.
AA amyloidosis invariably has been associated with fibrillar deposits of the acute phase high-density lipoprotein serum amyloid A isotypes SAA1 and SAA2. We now report the first case in a patient with no antecedent history of a chronic inflammatory or neoplastic process whose pathologic renal deposits were comprised of a mutated form of the constitutively expressed serum amyloid A4 (SAA4) protein. Analyses by tandem mass spectrometry of amyloid extracted from kidney biopsies revealed a component identical in sequence to the N-terminal portion of SAA4, except for the substitution of glycine for tryptophan at position 22 (W22G). Sequencing of genomic DNA using SAA4-specific primers showed a TGG to GGG transversion in codon 22 that accounted for the observed modification. Confirmation of the SAA4 nature of the amyloid was obtained immunohistochemically. Notably, only wild-type SAA4 was detected by mass spectrometry in the patient's serum and its concentration was within normal limits. Given the substitution of an amino acid lacking a side chain for a bulky residue, we posit that the W22G alteration would profoundly affect SAA4 stability, rendering it amyloidogenic. Our studies provide the first evidence for a novel type of AA amyloidosis in which the fibrils were formed from a mutated SAA4 protein.
Human Immunology and Cancer Program, Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, USA.
Charles L
CL
Murphy
Shuching
S
Wang
Daniel P
DP
Kestler
Fred A
FA
Stevens
Deborah T
DT
Weiss
Alan
A
Solomon
D000595:Amino Acid Sequence; D000686:Amyloidosis / Q000378:metabolism*; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D006801:Humans; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000378:metabolism*; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D000685:Serum Amyloid A Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
D017931:DNA Primers; C094771:SAA4 protein, human; D000685:Serum Amyloid A Protein