The New Apolipoprotein A-I Variant Leu174 → Ser Causes Hereditary Cardiac Amyloidosis, and the Amyloid Fibrils Are Constituted by the 93-Residue N-Terminal Polypeptide

Abstract

We identified a novel missense mutation in the apolipoprotein A-I gene, T2069C Leu(174) --> Ser, in a patient affected by familial systemic nonneuropathic amyloidosis. The amyloid deposits mostly affected the heart of the proband, who underwent transplantation for end-stage congestive heart failure. Amyloid fibrils of myocardial and periumbilical fat samples immunoreacted exclusively with anti-ApoA-I antibodies. Amyloid fibrils extracted from the heart were constituted, according to amino acid sequencing and mass spectrometry analysis, by an amino-terminal polypeptide ending at Val(93) of apolipoprotein A-I (apoA-I); no other significant fragments were detected. The mutation segregates with the disease; it was demonstrated in the proband and in an affected uncle and excluded in three healthy siblings. The plasma levels of high-density lipoprotein and apoA-I were significantly lower in the patient than in unaffected individuals. This represents the first case of familial apoA-I amyloidosis in which the mutation is outside the polypeptide fragment deposited as fibrils. Visualization of the mutation in the three-dimensional structure of lipid-free apoA-I, composed of four identical polypeptide chains, indicates that position 174 of one chain is located near position 93 of an adjacent chain and suggests that the amino acid replacement in position 174 is permissive for a proteolytic split at the C-terminal of Val(93).

Infertility and Hypergonadotropic Hypogonadism as First Evidence of Hereditary Apolipoprotein A-I Amyloidosis

“…These data strengthen and expand previous descriptions of single patients in whom testicular failure was reported in the medical history several years before a diagnosis of cardiac 9 or visceral 11,12 apoA-I amyloidosis was made.…”

“…8 Similarly testicular biopsy showed amyloid deposits several years before the occurrence of severe amyloid cardiomyopathy in a patient carrying the leucine 174 serine mutation of apoA-I. 9 ApoA-I, the major component of high density lipoproteins, can cause systemic amyloidosis at the presence of specific amino acid replacements. A total of 12 amyloidogenic apoA-I variants have been identified to date.…”

Amyloidogenicity and Clinical Phenotype Associated with Five Novel Mutations in Apolipoprotein A-I

“…35 Although the precise mechanism for the amyloidogenicity of variant apoAI remains unclear, it has been shown that mutated apoAI undergoes proteolytic cleavage releasing the amyloidogenic N-terminal fragment from the fulllength protein. 5,7,9 There are now 19 mutations in the APOAI gene known to be association with hereditary systemic apoAI amyloidosis, including the four novel amyloidogenic variants described here ( Table 1). The phenotype of apoAI amyloidosis may be fairly aggressive and present in teenagers with CKD, hepatomegaly, cardiomyopathy, and sometimes neuropathy 19,44 or may be extremely indolent and clinically insignificant.…”

“…The phenotype of apoAI amyloidosis may be fairly aggressive and present in teenagers with CKD, hepatomegaly, cardiomyopathy, and sometimes neuropathy 19,44 or may be extremely indolent and clinically insignificant. Interestingly, most C-terminal variants seem to be associated with hoarseness due to laryngeal amyloid deposits (Table 1), 7,9,10,20,40 although there is even substantial heterogeneity in the age at onset and clinical manifestations between patients with identical mutations. G26R, which is the most frequently reported amyloidogenic apoAI variant among Northern Europeans, is associated with amyloid de- apart from that in an Italian family with laryngeal, cardiac, and skin amyloidosis who carried the Leu90Pro apoAI variant.…”

“…105200) was coined by Ostertag 1 in 1932 following the discovery of two families with dominantly inherited renal amyloidosis. Mutations in the genes encoding apolipoprotein A-I (apoAI), [2][3][4][5][6][7][8][9][10][11][12] apolipoprotein A-II (apoAII), 13 fibrinogen A␣-chain, 14 -17 and lysozyme 18 have since been identified as the cause of hereditary renal amyloidosis in different kindreds (Online Mendelian Inheritance of Man no. 105200).…”