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(American Journal of Pathology. 1999;154:221-227.)
© 1999 American Society for Investigative Pathology

Regular Articles

Hereditary Amyloid Cardiomyopathy Caused by a Variant Apolipoprotein A1

Ladan Hamidi Asl* , Juris J. Liepnieks , Kamran Hamidi Asl , Tomoyuki Uemichi , Georges Moulin§ , Emmanuel Desjoyaux¶ , Robert Loire|| , Marc Delpech* , Gilles Grateau** and Merrill D. Benson

From ICGM-CHU Cochin,* Laboratoire de Biochimie et Biologie Moléculaire EA1501, Paris, France; the Department of Medical and Molecular Genetics, Indiana University School of Medicine, and the Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana; the Service de Dermatologie,§ Hôpital de l'Antiquaille, and the Laboratoire d'Anatomie Pathologique,^|| Hôpital Cardio-vasculaire Louis Pradel, Lyon, France; the Service de Cardiologie,^¶ Centre Hospitalier Général, Annecy, France; and the Service de Médecine Interne,** L'Hôtel Dieu de Paris, Paris, France

Autosomal dominant hereditary amyloidosis with a unique cutaneous and cardiac presentation and death from heart failure by the sixth or seventh decade was found to be associated with a previously unreported point mutation (thymine to cytosine, nt 1389) in exon 4 of the apolipoprotein A1 (apoA1) gene. The predicted substitution of proline for leucine at amino acid position 90 was confirmed by structural analysis of amyloid protein isolated from cardiac deposits of amyloid. The subunit protein is composed exclusively of NH₂-terminal fragments of the variant apoA1 with the longest ending at residue 94 in the wild-type sequence. Amyloid fibrils derived from four previously described apoA1 variants are composed of similar fragments with carboxyl-terminal heterogeneity, but contrary to those variants, which all carry one extra positive charge, the substitution Leu90Pro does not result in any charge modification. It is unlikely, therefore, that amyloid fibril formation is related to change of charge for a specific residue of the precursor protein. This is in agreement with studies on transthyretin amyloidosis in which no unifying factor such as change of charge for amino acid residues has been noted.

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