http://informahealthcare.com/amy ISSN: 1350-6129 (print), 1744-2818 (electronic) Amyloid, 2014; 21(4): 221–224 ! 2014 Informa UK Ltd. DOI: 10.3109/13506129.2014.964858
EDITORIAL
Nomenclature 2014: Amyloid fibril proteins and clinical classification of the amyloidosis
Amyloid Downloaded from informahealthcare.com by University of California San Francisco on 12/13/14 For personal use only.
Introduction The Nomenclature Committee of the International Society of Amyloidosis (ISA) met during the XIVth Symposium of the Society, April 27–May 1, 2014, Indianapolis, IN, to assess and formulate recommendations for nomenclature for amyloid fibril proteins and the clinical classification of the amyloidoses. To date, there are 31 known extracellular fibril proteins in humans (Table 1), two of which are iatrogenic in nature and nine of which have been identified also in animals (Table 2). A large number of intracellular protein inclusions displaying some of the properties of amyloid ‘‘intracellular amyloid’’ has been reported (Table 3). Amyloid fibril nomenclature is based on the chemical identity of the amyloid fibril forming protein; clinical classification of the amyloidosis should be as well. An amyloid fibril protein is defined as follows: the protein must occur in body tissue deposits and exhibit affinity for Congo red and green, yellow or orange birefringence when the Congo red-stained deposits are viewed with polarized light. Furthermore, the chemical identity of the protein must have been unambiguously characterized by protein sequence analysis when possible. In general, it is insufficient to identify a mutation in the gene of a candidate amyloid protein without confirming the variant amino acid in the amyloid fibril protein.
Background When the chemical diversity of amyloid and amyloidosis became apparent in the mid-1970s, participants in the International Symposium on Amyloidosis, Helsinki, Finland, 1974, recognized the need for a system of nomenclature for proteins related to amyloidosis and appointed a Nomenclature Committee [1]. Since then, the Nomenclature Committee has convened in association with the international symposia and has published recommendations when indicated by advances in the field [2–9]. A synopsis of nomenclature guidelines established from previous recommendations is presented here, followed by current recommendations from the XIVth International Symposium on Amyloidosis.
Definition of an amyloid fibril An amyloid fibril protein is a protein that is deposited as insoluble fibrils, mainly in the extracellular spaces of organs and tissues as a result of sequential changes in protein folding that result in a condition known as amyloidosis.
An amyloid fibril protein occurs in tissue deposits as rigid, non-branching fibrils approximately 10 nm in diameter. The fibrils bind the dye Congo red and exhibit green, yellow or orange birefringence when the stained deposits are viewed by polarization microscopy. When isolated from tissues and analyzed by X-ray diffraction, the fibrils exhibit a characteristic cross b diffraction pattern. To be included in the official ISA Amyloid Fibril Protein Nomenclature List (Tables 1 and 2), an amyloid fibril protein must have been unambiguously characterized by protein sequence analysis when possible and described in a peer-reviewed journal.
Inclusions with aggregated proteins Intracellular protein inclusions have been described that, according to the present nomenclature, are not included in the list of amyloid proteins. However, at least one of them, the neurofibrillary tangles, has fibrillar structure, a cross b-sheet X-ray diffraction pattern and binds Congo red and exhibits green birefringence. The tangles may therefore be called ‘‘intracellular amyloid’’, although they presently are not included in the formal list of characterized amyloids. Lewy bodies in the brain with Parkinson’s disease consist of fine amyloid-like fibrils, and are, at least sometimes, stained with Congo red and exhibit birefringence. Other inclusions have some, but not all, of these properties. Some of the intracellular inclusions that have been biochemically characterized, at least partly, are included in Table 3.
Amyloid fibril protein nomenclature The amyloid fibril protein is designated protein A and followed by a suffix that is an abbreviated form of the parent or precursor protein name. For example, when amyloid fibrils are derived from immunoglobulin light chains, the amyloid fibril protein is AL and the disease is AL amyloidosis. AL is not a disease; AL is the disease-causing protein. Traditionally, amyloid fibril protein variants have been named according to the substitution or deletion in the mature protein, e.g. ATTRV30M or ALysI56T and this principle should continue to be followed. However, to be consistent with the recommendations of the Nomenclature Working Group for human gene mutations, numbering corresponding to the unprocessed gene product (including signal peptide and propeptides) can be given in parentheses, e.g. (p. TTRV50M)
222
J. D. Sipe et al.
Amyloid, 2014; 21(4): 221–224
Table 1. Amyloid fibril proteins and their precursors in humana.
Fibril protein AL AH AA ATTR Ab2M
Amyloid Downloaded from informahealthcare.com by University of California San Francisco on 12/13/14 For personal use only.
AApoAI AApoAII AApoAIV AGel ALys ALECT2 AFib ACys ABri ADan* Ab APrP ACal AIAPP AANF APro AIns ASPCz AGal7 ACor AMed Aker ALac AOAAP ASem1 AEnf
Systemic and/or localized
Acquired or hereditary
Immunoglobulin Light Chain Immunoglobulin Heavy Chain (Apo) Serum Amyloid A Transthyretin, wild type
S, L S, L S S
A, H A A A
Transthyretin, variants b2-Microglobulin, wild type b2-Microglobulin, variant Apolipoprotein A I, variants
S L S S
H A H H
Apolipoprotein A II, variants Apolipoprotein A IV, wild type Gelsolin, variants Lysozyme, variants Leukocyte Chemotactic Factor-2 Fibrinogen a, variants Cystatin C, variants ABriPP, variants ADanPP, variants Ab protein precursor, wild type Ab protein precursor, variant Prion protein, wild type Prion protein variants (Pro)calcitonin Islet Amyloid Polypeptidey Atrial Natriuretic Factor Prolactin Insulin Lung Surfactant Protein Galectin 7 Corneodesmosin Lactadherin Kerato-epithelin Lactoferrin Odontogenic Ameloblast-Associated Protein Semenogelin 1 Enfurvitide
S S S S S S S S L L L L L L L L L L L L L L L L L
H A H H A H H H H A H A H A A A A A A A A A A A A
All organs except CNS All organs except CNS All organs except CNS Heart mainly in males, Ligaments, Tenosynovium PNS, ANS, heart, eye, leptomen. Musculoskeletal System ANS Heart, liver, kidney, PNS, testis, larynx (C terminal variants), skin (C terminal variants) Kidney Kidney medulla and systemic PNS, cornea Kidney Kidney, primarily Kidney, primarily PNS, skin CNS CNS CNS CNS CJD, Fatal insomnia CJD, GSS syndrome, Fatal insomnia C-cell thyroid tumors Islets of Langerhans, Insulinomas Cardiac atria Pituitary prolactinomas, aging pituitary Iatrogenic, local injection Lung Skin Cornified epithelia, Hair follicles Senile aortic, Media Cornea, hereditary Cornea Odontogenic tumors
L L
A A
Vesicula seminalis Iatrogenic
Precursor protein
Target organs
a
Proteins are listed, when possible, according to relationship. Thus, apolipoproteins are grouped together, as are polypeptide hormones. *ADan is the product of the same gene as ABri. yAlso called amylin. zNot proven by amino acid sequence analysis.
Table 2. Amyloid fibril proteins and their precursors in animals.
Fibril protein
Precursor protein
Systemic and/ or localized
AL AA
Immunoglobulin Light Chain (Apo) Serum Amyloid A
S, L S
AApoAI AApoAII ATTR AFib Ab AIAPP AIns ACas
Apolipoprotein AI Apolipoprotein AII Transthyretin, variant Fibrinogen Aa Ab precursor protein Islet Amyloid Polypeptide Insulin A-S2C casein
S S S S L L L L
or (p. LysI75T) [10] following the designation of the mature protein. In addition, it is the recommendation of geneticists to use the three-letter amino acid code and, when DNA sequencing
Affected organs or syndrome
Species
Plasmacytoma Chronic Inflammation or Infections Age-related Age-related Age-related Spleen, Liver Age-related Islets of Langerhans, Insulinoma Islets of Langerhans Mammary gland
Cat, Horse Mouse, Cat, Cow, Dog, Duck, Guinea pig, etc. Dog Mouse Vervet monkey Stone marten Dog, Sheep, Wolverine Apes, Cat, Racoon Octodon degus Cow
only has been performed (most common these days), the mutation should appear within brackets. Thus, TTRV30M should be TTR c.(Val50Met) when no protein or RNA sequencing has been performed. However, as amyloid
Amyloid Nomenclature 2014
DOI: 10.3109/13506129.2014.964858
223
Table 3. Intracellular inclusions with known biochemical composition, with or without amyloid properties. Inclusion name
Site
Lewy bodies Huntington bodies
Neurons intracytoplasmic Neurons intranuclear
Hirano bodies Collins bodies Not specified Neurofibrillary tangles
Neurons Neurons Neurons, many different cells Neurons intracytoplasmic
Protein nature a-synuclein* Polyq expanded Huntingtin Actin Neuroserpin Ferritin Tau
Examples of associated disease Parkinson’s disease Huntington’s disease Neurodegenerative disorders Forms of familial presenile dementia Form of familial neurodegenerative disorder Alzheimer disease, fronto-temporal dementia, aging, other cerebral conditions
Amyloid Downloaded from informahealthcare.com by University of California San Francisco on 12/13/14 For personal use only.
*Simplified. Additional components may exist.
nomenclature is applicable to selective mutations that appear in the mature protein and not the primary translation product, we recommend use of the single letter amino code and the sequence numbering of the mature protein when reporting studies on amyloid proteins.
Biophysical amyloid The designation ‘‘amyloid’’, first used in botany, was applied by Virchow, originally to corpora amylacea in the brain and later for the tissue deposits of systemic amyloidosis. Subsequently, the concept of amyloid was expanded to denote diverse localized tissue deposits (e.g. in Alzheimer’s disease or type 2 diabetes) with similar homogeneous appearance in light microscopy and with the same tinctorial and physical properties. The definition of amyloid has now been broadened in that it is regularly used by biochemists and biophysicists for naturally occurring and synthetic protein fibrils with some amyloid properties. In order to avoid confusion, the ISA Nomenclature Committee has recommended the use of ‘‘amyloid-like’’ for synthetic fibrils [7].
Functional amyloid Another nomenclature related consideration has emerged with the use of the concept ‘‘functional amyloid’’. Structurally robust, protease resistant b-sheet fibrillar assemblies occur widely in nature, particularly in invertebrates, e.g. bacterial biofilms. In addition, it has been suggested that some human structures, such as the p-mel framework in melanosomes and the organization of at least some polypeptide hormones when stored in secretory vesicles, have an amyloid fibril structure [11]. These more broadly applied circumstances have made it increasingly important to use clear definitions when using the word ‘‘amyloid’’. To the group of ‘‘functional amyloids’’ may be added the recently described fibrillar aggregates of fragments of prostatic acidic phosphatase (PAP). These fibrils, which have been termed Semen-derived Enhancer of Virus Infection (SEVI), are believed to play an active role in human immunodeficiency virus infections [12] and have been shown to form in vivo [13]. There is a first report that TTR aggregation plays a role in the pathogenesis of pre-eclampsia and that the native form prevents the onset of disease in a preclinical mouse model [14].
Amyloidosis syndrome nomenclature The amyloidosis syndrome is named after the amyloid fibril protein, e.g. AL amyloidosis (localized or systemic), wild-type ATTR amyloidosis or hereditary ATTRV30M (p. TTRV50M) amyloidosis. This nomenclature has been adopted by the World Health Organization [15] and consistently recommended by the ISA Nomenclature Committee [1–9]. It is important to use chemically based nomenclature, e.g. ATTRV30M (p. TTRV50M) and ATTRY78F(p. TTRY98F) to avoid confusion with the more frequently occurring AL amyloidosis, for which the treatment plan would be markedly different. The terms ‘‘hereditary amyloidosis’’ and ‘‘familial amyloidosis’’ refer to different entities. The hereditary amyloidoses, e.g. with ATTR or AFib proteins, result from a mutation in the fibril protein gene itself, while other amyloidoses, e.g. AA amyloidosis can occur in a familial setting due to mutations in genes expressing non-amyloid proteins. At the meeting, the first example of hereditary AL amyloidosis of kappa type was presented [16]. Synonyms and terminology used in the past when the chemical diversity of amyloid fibril proteins was unrecognized remain in use today, but are not particularly useful. For example, synonyms for hereditary ATTR amyloidosis that are or have been used include Familial Amyloid Polyneuropathy Type I (Portuguese–Swedish–Japanese Type), Familial Amyloid Polyneuropathy Type II (Indiana/Swiss or Maryland/German Type), Leptomeningeal Amyloidosis, Familial Amyloid Cardiomyopathy, Familial Oculoleptomeningeal Amyloidosis (FOLMA). As indicated above, it is strongly recommended to always refer to the syndrome according to the name of the protein. However, the term familial amyloid polyneuropathy (FAP) is widely used in the neurology literature and it may be included as appropriate. The designation senile systemic amyloidosis (SSA) was coined when it became clear that this is a systemic disease with a specific amyloid protein and not only a cardiac disease that occurs particularly in old age [17]. It was later shown that the fibril protein in SSA is derived from wild-type TTR [18] and that the disease can occur at younger age. It is therefore the committee’s recommendation to use ‘‘wild-type ATTR (ATTRwt) amyloidosis’’ instead of SSA. In a transition period both SSA and ATTRwt amyloidosis can be used simultaneously in order to avoid confusion.
224
J. D. Sipe et al.
The clinical classification of AL amyloidosis as primary amyloidosis and AA amyloidosis as secondary amyloidosis is ambiguous and outdated and it has long been recommended that these designations not to be used [2].
Amyloid Downloaded from informahealthcare.com by University of California San Francisco on 12/13/14 For personal use only.
Oligomeric fibril precursors There was discussion of terminology and nomenclature for prefibrillar amyloid species, including protofibrils and oligomers. This is presently a very confusing area. This matter will require further consideration and it was noted that the ISA nomenclature perspective is an in vivo one, although in vitro studies serve to illuminate pathogenesis and will require/ benefit from a more precise system of nomenclature. Consequently, nomenclature suggestions have to wait until the nature of oligomeric fibril precursors becomes clear as does the nature of their activity in vivo.
Committee recommendations The committee recommended changes that are reflected in Table 1: (1) correction of the precursor of ACor to corneodesmosin, (2) standardization of acronyms to use all upper case letters except when a single syllable of the precursor or fibril is used to name the protein, (3) removal of the localized designation for ATTR, as this has not been well documented and (4) addition of AEnf as a recently described iatrogenic form of localized amyloidosis (Table 1 [19]). Jean D. Sipe Department of Biochemistry (Retired), Boston University School of Medicine, 1 Longfellow Place, Boston, MA 02114 USA. E-mail: [email protected] Merrill D. Benson Department of Pathology and Laboratory Medicine Indiana University School of Medicine Indianapolis, IN, USA Joel N. Buxbaum Department of Molecular and Experimental Medicine The Scripps Research Institute, La Jolla, CA, USA Shu-ichi Ikeda Department of Medicine (Neurology and Rheumatology) Shinshu University School of Medicine, Matsumoto, Japan Giampaolo Merlini Amyloid Research and Treatment Center, University of Pavia and IRCCS Policlinico San Matteo, Pavia, Italy Maria J. M. Saraiva Amyloid Unit, Institute of Molecular and Cellular Biology University of Porto, Porto, Portugal Per Westermark Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
Acknowledgments The ISA Nomenclature Committee thanks Dr. Maria Picken for critical discussion and insightful recommendations on the need for more precise nomenclature.
Amyloid, 2014; 21(4): 221–224
Declaration of interest The authors report no conflicts of interest.
References 1. Cohen AS, Franklin EC, Glenner GG. Nomenclature. In: Wegelius O, Pasternack A, eds. Amyloidosis. London: Academic Press; 1976:ix. 2. Benditt EP, Cohen AS, Costa PP, Franklin EC, Glenner GG, Husby G, Mandema E, et al. Guidelines for nomenclature. In: Glenner GG, Costa PP, Freitas AF, eds. Amyloid and amyloidosis. Amsterdam: Excerpta Medica; 1980:XI–XII. 3. Husby G, Araki S, Benditt EP, Benson MD, Cohen AS, Frangione B, Glenner GG, et al. The 1990 guidelines for nomenclature and classification of amyloid and amyloidosis. In: Natvig JB, Fo¨rre O, Husby G, Husebekk A, Skogen B, Sletten K, Westermark P, eds. Amyloid and amyloidosis 1990. Dordrecht: Kluwer; 1991:7–11. 4. Westermark P. Classification of amyloid fibril proteins and their precursors: an ongoing discussion. Amyloid 1997;4:216–18. 5. Westermark P, Benson MD, Buxbaum JN, Cohen AS, Frangione B, Ikeda S, Masters CL, et al. Amyloid fibril protein nomenclature. Amyloid 2002;9:197–200. 6. Westermark P, Benson MD, Buxbaum JN, Cohen AS, Frangione B, Ikeda S-I, Masters CL, et al. Amyloid: toward terminology classification. Report from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid 2005;12:1–4. 7. Westermark P, Benson MD, Buxbaum JN, Cohen AS, Frangione B, Ikeda S-I, Masters CL, et al. A primer of amyloid nomenclature. Amyloid 2007;14:179–83. 8. Sipe JD, Benson MD, Buxbaum JN, Ikeda S-I, Merlini G, Saraiva MJM, Westermark P. Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis. Amyloid 2012;19: 167–70. 9. Sipe JD, Benson MD, Buxbaum JN, Ikeda S-I, Merlini G, Saraiva MJM, Westermark P. Amyloid fibril protein nomenclature: 2012 recommendations from the nomenclature committee of the International Society of Amyloidosis. Amyloid 2010;17:101–4. 10. den Dunnen JT, Antonarakis SE. Nomenclature for the description of human sequence variations. Hum Mutat 2000;15:7–12. 11. Maury CPJ. The emerging concept of functional amyloid (review). J Intern Med 2009;265:329–34. 12. Mu¨nch J, Rucker E, Standker L, Adermann K, Goffinet Ch, Schindler M, Wildum S, et al. Semen-derived amyloid fibrils drastically enhance HIV infection. Cell 2007;131: 1059–71. 13. Usmani SM, Zirafi O, Mu¨ller JA, Sandi-Monroy NL, Yadav JK, Meier C, Weil T, et al. Direct visualization of HIV-enhancing endogenous amyloid fibrils in human semen. Nat Commun 2014;5: Article ID:3508. 14. Kalkunte SS, Neubeck S, Norris WE, Cheng SB, Kostadinov S, Vu Hoang D, Ahmed A, et al. Transthyretin is dysregulated in preeclampsia, and its native form prevents the onset of disease in a preclinical mouse model. Am J Pathol 2013;183:1425–36. 15. WHO-IUIS Nomenclature Sub-Committee. Nomenclature of amyloid and amyloidosis. Bull World Health Organ 1993;71:105–12. 16. Benson MD, Liepnicks JJ, Kluve-Beckerman B. Hereditary systemic immunoglobulin light-chain (AL) amyloidosis. XIVth Int Symp Amyloidosis, April 27–May 1, 2014, Indianapolis, IN. 17. Pitka¨nen P, Westermark P, Cornwell III GG. Senile systemic amyloidosis. Am J Path 1984;117:391–9. 18. Westermark P, Sletten K, Johansson B, Cornwell III GG. Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc Natl Acad Sci USA 1990;87:2843–5. 19. D’Souza A, Theis JD, Vrana JA, Dogan A. Pharmaceutical amyloidosis associated with subcutaneous insulin and enfuvirtide administration. Amyloid 2014;21:71–5.
EDITORIAL
Nomenclature 2014: Amyloid fibril proteins and clinical classification of the amyloidosis
Amyloid Downloaded from informahealthcare.com by University of California San Francisco on 12/13/14 For personal use only.
Introduction The Nomenclature Committee of the International Society of Amyloidosis (ISA) met during the XIVth Symposium of the Society, April 27–May 1, 2014, Indianapolis, IN, to assess and formulate recommendations for nomenclature for amyloid fibril proteins and the clinical classification of the amyloidoses. To date, there are 31 known extracellular fibril proteins in humans (Table 1), two of which are iatrogenic in nature and nine of which have been identified also in animals (Table 2). A large number of intracellular protein inclusions displaying some of the properties of amyloid ‘‘intracellular amyloid’’ has been reported (Table 3). Amyloid fibril nomenclature is based on the chemical identity of the amyloid fibril forming protein; clinical classification of the amyloidosis should be as well. An amyloid fibril protein is defined as follows: the protein must occur in body tissue deposits and exhibit affinity for Congo red and green, yellow or orange birefringence when the Congo red-stained deposits are viewed with polarized light. Furthermore, the chemical identity of the protein must have been unambiguously characterized by protein sequence analysis when possible. In general, it is insufficient to identify a mutation in the gene of a candidate amyloid protein without confirming the variant amino acid in the amyloid fibril protein.
Background When the chemical diversity of amyloid and amyloidosis became apparent in the mid-1970s, participants in the International Symposium on Amyloidosis, Helsinki, Finland, 1974, recognized the need for a system of nomenclature for proteins related to amyloidosis and appointed a Nomenclature Committee [1]. Since then, the Nomenclature Committee has convened in association with the international symposia and has published recommendations when indicated by advances in the field [2–9]. A synopsis of nomenclature guidelines established from previous recommendations is presented here, followed by current recommendations from the XIVth International Symposium on Amyloidosis.
Definition of an amyloid fibril An amyloid fibril protein is a protein that is deposited as insoluble fibrils, mainly in the extracellular spaces of organs and tissues as a result of sequential changes in protein folding that result in a condition known as amyloidosis.
An amyloid fibril protein occurs in tissue deposits as rigid, non-branching fibrils approximately 10 nm in diameter. The fibrils bind the dye Congo red and exhibit green, yellow or orange birefringence when the stained deposits are viewed by polarization microscopy. When isolated from tissues and analyzed by X-ray diffraction, the fibrils exhibit a characteristic cross b diffraction pattern. To be included in the official ISA Amyloid Fibril Protein Nomenclature List (Tables 1 and 2), an amyloid fibril protein must have been unambiguously characterized by protein sequence analysis when possible and described in a peer-reviewed journal.
Inclusions with aggregated proteins Intracellular protein inclusions have been described that, according to the present nomenclature, are not included in the list of amyloid proteins. However, at least one of them, the neurofibrillary tangles, has fibrillar structure, a cross b-sheet X-ray diffraction pattern and binds Congo red and exhibits green birefringence. The tangles may therefore be called ‘‘intracellular amyloid’’, although they presently are not included in the formal list of characterized amyloids. Lewy bodies in the brain with Parkinson’s disease consist of fine amyloid-like fibrils, and are, at least sometimes, stained with Congo red and exhibit birefringence. Other inclusions have some, but not all, of these properties. Some of the intracellular inclusions that have been biochemically characterized, at least partly, are included in Table 3.
Amyloid fibril protein nomenclature The amyloid fibril protein is designated protein A and followed by a suffix that is an abbreviated form of the parent or precursor protein name. For example, when amyloid fibrils are derived from immunoglobulin light chains, the amyloid fibril protein is AL and the disease is AL amyloidosis. AL is not a disease; AL is the disease-causing protein. Traditionally, amyloid fibril protein variants have been named according to the substitution or deletion in the mature protein, e.g. ATTRV30M or ALysI56T and this principle should continue to be followed. However, to be consistent with the recommendations of the Nomenclature Working Group for human gene mutations, numbering corresponding to the unprocessed gene product (including signal peptide and propeptides) can be given in parentheses, e.g. (p. TTRV50M)
222
J. D. Sipe et al.
Amyloid, 2014; 21(4): 221–224
Table 1. Amyloid fibril proteins and their precursors in humana.
Fibril protein AL AH AA ATTR Ab2M
Amyloid Downloaded from informahealthcare.com by University of California San Francisco on 12/13/14 For personal use only.
AApoAI AApoAII AApoAIV AGel ALys ALECT2 AFib ACys ABri ADan* Ab APrP ACal AIAPP AANF APro AIns ASPCz AGal7 ACor AMed Aker ALac AOAAP ASem1 AEnf
Systemic and/or localized
Acquired or hereditary
Immunoglobulin Light Chain Immunoglobulin Heavy Chain (Apo) Serum Amyloid A Transthyretin, wild type
S, L S, L S S
A, H A A A
Transthyretin, variants b2-Microglobulin, wild type b2-Microglobulin, variant Apolipoprotein A I, variants
S L S S
H A H H
Apolipoprotein A II, variants Apolipoprotein A IV, wild type Gelsolin, variants Lysozyme, variants Leukocyte Chemotactic Factor-2 Fibrinogen a, variants Cystatin C, variants ABriPP, variants ADanPP, variants Ab protein precursor, wild type Ab protein precursor, variant Prion protein, wild type Prion protein variants (Pro)calcitonin Islet Amyloid Polypeptidey Atrial Natriuretic Factor Prolactin Insulin Lung Surfactant Protein Galectin 7 Corneodesmosin Lactadherin Kerato-epithelin Lactoferrin Odontogenic Ameloblast-Associated Protein Semenogelin 1 Enfurvitide
S S S S S S S S L L L L L L L L L L L L L L L L L
H A H H A H H H H A H A H A A A A A A A A A A A A
All organs except CNS All organs except CNS All organs except CNS Heart mainly in males, Ligaments, Tenosynovium PNS, ANS, heart, eye, leptomen. Musculoskeletal System ANS Heart, liver, kidney, PNS, testis, larynx (C terminal variants), skin (C terminal variants) Kidney Kidney medulla and systemic PNS, cornea Kidney Kidney, primarily Kidney, primarily PNS, skin CNS CNS CNS CNS CJD, Fatal insomnia CJD, GSS syndrome, Fatal insomnia C-cell thyroid tumors Islets of Langerhans, Insulinomas Cardiac atria Pituitary prolactinomas, aging pituitary Iatrogenic, local injection Lung Skin Cornified epithelia, Hair follicles Senile aortic, Media Cornea, hereditary Cornea Odontogenic tumors
L L
A A
Vesicula seminalis Iatrogenic
Precursor protein
Target organs
a
Proteins are listed, when possible, according to relationship. Thus, apolipoproteins are grouped together, as are polypeptide hormones. *ADan is the product of the same gene as ABri. yAlso called amylin. zNot proven by amino acid sequence analysis.
Table 2. Amyloid fibril proteins and their precursors in animals.
Fibril protein
Precursor protein
Systemic and/ or localized
AL AA
Immunoglobulin Light Chain (Apo) Serum Amyloid A
S, L S
AApoAI AApoAII ATTR AFib Ab AIAPP AIns ACas
Apolipoprotein AI Apolipoprotein AII Transthyretin, variant Fibrinogen Aa Ab precursor protein Islet Amyloid Polypeptide Insulin A-S2C casein
S S S S L L L L
or (p. LysI75T) [10] following the designation of the mature protein. In addition, it is the recommendation of geneticists to use the three-letter amino acid code and, when DNA sequencing
Affected organs or syndrome
Species
Plasmacytoma Chronic Inflammation or Infections Age-related Age-related Age-related Spleen, Liver Age-related Islets of Langerhans, Insulinoma Islets of Langerhans Mammary gland
Cat, Horse Mouse, Cat, Cow, Dog, Duck, Guinea pig, etc. Dog Mouse Vervet monkey Stone marten Dog, Sheep, Wolverine Apes, Cat, Racoon Octodon degus Cow
only has been performed (most common these days), the mutation should appear within brackets. Thus, TTRV30M should be TTR c.(Val50Met) when no protein or RNA sequencing has been performed. However, as amyloid
Amyloid Nomenclature 2014
DOI: 10.3109/13506129.2014.964858
223
Table 3. Intracellular inclusions with known biochemical composition, with or without amyloid properties. Inclusion name
Site
Lewy bodies Huntington bodies
Neurons intracytoplasmic Neurons intranuclear
Hirano bodies Collins bodies Not specified Neurofibrillary tangles
Neurons Neurons Neurons, many different cells Neurons intracytoplasmic
Protein nature a-synuclein* Polyq expanded Huntingtin Actin Neuroserpin Ferritin Tau
Examples of associated disease Parkinson’s disease Huntington’s disease Neurodegenerative disorders Forms of familial presenile dementia Form of familial neurodegenerative disorder Alzheimer disease, fronto-temporal dementia, aging, other cerebral conditions
Amyloid Downloaded from informahealthcare.com by University of California San Francisco on 12/13/14 For personal use only.
*Simplified. Additional components may exist.
nomenclature is applicable to selective mutations that appear in the mature protein and not the primary translation product, we recommend use of the single letter amino code and the sequence numbering of the mature protein when reporting studies on amyloid proteins.
Biophysical amyloid The designation ‘‘amyloid’’, first used in botany, was applied by Virchow, originally to corpora amylacea in the brain and later for the tissue deposits of systemic amyloidosis. Subsequently, the concept of amyloid was expanded to denote diverse localized tissue deposits (e.g. in Alzheimer’s disease or type 2 diabetes) with similar homogeneous appearance in light microscopy and with the same tinctorial and physical properties. The definition of amyloid has now been broadened in that it is regularly used by biochemists and biophysicists for naturally occurring and synthetic protein fibrils with some amyloid properties. In order to avoid confusion, the ISA Nomenclature Committee has recommended the use of ‘‘amyloid-like’’ for synthetic fibrils [7].
Functional amyloid Another nomenclature related consideration has emerged with the use of the concept ‘‘functional amyloid’’. Structurally robust, protease resistant b-sheet fibrillar assemblies occur widely in nature, particularly in invertebrates, e.g. bacterial biofilms. In addition, it has been suggested that some human structures, such as the p-mel framework in melanosomes and the organization of at least some polypeptide hormones when stored in secretory vesicles, have an amyloid fibril structure [11]. These more broadly applied circumstances have made it increasingly important to use clear definitions when using the word ‘‘amyloid’’. To the group of ‘‘functional amyloids’’ may be added the recently described fibrillar aggregates of fragments of prostatic acidic phosphatase (PAP). These fibrils, which have been termed Semen-derived Enhancer of Virus Infection (SEVI), are believed to play an active role in human immunodeficiency virus infections [12] and have been shown to form in vivo [13]. There is a first report that TTR aggregation plays a role in the pathogenesis of pre-eclampsia and that the native form prevents the onset of disease in a preclinical mouse model [14].
Amyloidosis syndrome nomenclature The amyloidosis syndrome is named after the amyloid fibril protein, e.g. AL amyloidosis (localized or systemic), wild-type ATTR amyloidosis or hereditary ATTRV30M (p. TTRV50M) amyloidosis. This nomenclature has been adopted by the World Health Organization [15] and consistently recommended by the ISA Nomenclature Committee [1–9]. It is important to use chemically based nomenclature, e.g. ATTRV30M (p. TTRV50M) and ATTRY78F(p. TTRY98F) to avoid confusion with the more frequently occurring AL amyloidosis, for which the treatment plan would be markedly different. The terms ‘‘hereditary amyloidosis’’ and ‘‘familial amyloidosis’’ refer to different entities. The hereditary amyloidoses, e.g. with ATTR or AFib proteins, result from a mutation in the fibril protein gene itself, while other amyloidoses, e.g. AA amyloidosis can occur in a familial setting due to mutations in genes expressing non-amyloid proteins. At the meeting, the first example of hereditary AL amyloidosis of kappa type was presented [16]. Synonyms and terminology used in the past when the chemical diversity of amyloid fibril proteins was unrecognized remain in use today, but are not particularly useful. For example, synonyms for hereditary ATTR amyloidosis that are or have been used include Familial Amyloid Polyneuropathy Type I (Portuguese–Swedish–Japanese Type), Familial Amyloid Polyneuropathy Type II (Indiana/Swiss or Maryland/German Type), Leptomeningeal Amyloidosis, Familial Amyloid Cardiomyopathy, Familial Oculoleptomeningeal Amyloidosis (FOLMA). As indicated above, it is strongly recommended to always refer to the syndrome according to the name of the protein. However, the term familial amyloid polyneuropathy (FAP) is widely used in the neurology literature and it may be included as appropriate. The designation senile systemic amyloidosis (SSA) was coined when it became clear that this is a systemic disease with a specific amyloid protein and not only a cardiac disease that occurs particularly in old age [17]. It was later shown that the fibril protein in SSA is derived from wild-type TTR [18] and that the disease can occur at younger age. It is therefore the committee’s recommendation to use ‘‘wild-type ATTR (ATTRwt) amyloidosis’’ instead of SSA. In a transition period both SSA and ATTRwt amyloidosis can be used simultaneously in order to avoid confusion.
224
J. D. Sipe et al.
The clinical classification of AL amyloidosis as primary amyloidosis and AA amyloidosis as secondary amyloidosis is ambiguous and outdated and it has long been recommended that these designations not to be used [2].
Amyloid Downloaded from informahealthcare.com by University of California San Francisco on 12/13/14 For personal use only.
Oligomeric fibril precursors There was discussion of terminology and nomenclature for prefibrillar amyloid species, including protofibrils and oligomers. This is presently a very confusing area. This matter will require further consideration and it was noted that the ISA nomenclature perspective is an in vivo one, although in vitro studies serve to illuminate pathogenesis and will require/ benefit from a more precise system of nomenclature. Consequently, nomenclature suggestions have to wait until the nature of oligomeric fibril precursors becomes clear as does the nature of their activity in vivo.
Committee recommendations The committee recommended changes that are reflected in Table 1: (1) correction of the precursor of ACor to corneodesmosin, (2) standardization of acronyms to use all upper case letters except when a single syllable of the precursor or fibril is used to name the protein, (3) removal of the localized designation for ATTR, as this has not been well documented and (4) addition of AEnf as a recently described iatrogenic form of localized amyloidosis (Table 1 [19]). Jean D. Sipe Department of Biochemistry (Retired), Boston University School of Medicine, 1 Longfellow Place, Boston, MA 02114 USA. E-mail: [email protected] Merrill D. Benson Department of Pathology and Laboratory Medicine Indiana University School of Medicine Indianapolis, IN, USA Joel N. Buxbaum Department of Molecular and Experimental Medicine The Scripps Research Institute, La Jolla, CA, USA Shu-ichi Ikeda Department of Medicine (Neurology and Rheumatology) Shinshu University School of Medicine, Matsumoto, Japan Giampaolo Merlini Amyloid Research and Treatment Center, University of Pavia and IRCCS Policlinico San Matteo, Pavia, Italy Maria J. M. Saraiva Amyloid Unit, Institute of Molecular and Cellular Biology University of Porto, Porto, Portugal Per Westermark Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
Acknowledgments The ISA Nomenclature Committee thanks Dr. Maria Picken for critical discussion and insightful recommendations on the need for more precise nomenclature.
Amyloid, 2014; 21(4): 221–224
Declaration of interest The authors report no conflicts of interest.
References 1. Cohen AS, Franklin EC, Glenner GG. Nomenclature. In: Wegelius O, Pasternack A, eds. Amyloidosis. London: Academic Press; 1976:ix. 2. Benditt EP, Cohen AS, Costa PP, Franklin EC, Glenner GG, Husby G, Mandema E, et al. Guidelines for nomenclature. In: Glenner GG, Costa PP, Freitas AF, eds. Amyloid and amyloidosis. Amsterdam: Excerpta Medica; 1980:XI–XII. 3. Husby G, Araki S, Benditt EP, Benson MD, Cohen AS, Frangione B, Glenner GG, et al. The 1990 guidelines for nomenclature and classification of amyloid and amyloidosis. In: Natvig JB, Fo¨rre O, Husby G, Husebekk A, Skogen B, Sletten K, Westermark P, eds. Amyloid and amyloidosis 1990. Dordrecht: Kluwer; 1991:7–11. 4. Westermark P. Classification of amyloid fibril proteins and their precursors: an ongoing discussion. Amyloid 1997;4:216–18. 5. Westermark P, Benson MD, Buxbaum JN, Cohen AS, Frangione B, Ikeda S, Masters CL, et al. Amyloid fibril protein nomenclature. Amyloid 2002;9:197–200. 6. Westermark P, Benson MD, Buxbaum JN, Cohen AS, Frangione B, Ikeda S-I, Masters CL, et al. Amyloid: toward terminology classification. Report from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid 2005;12:1–4. 7. Westermark P, Benson MD, Buxbaum JN, Cohen AS, Frangione B, Ikeda S-I, Masters CL, et al. A primer of amyloid nomenclature. Amyloid 2007;14:179–83. 8. Sipe JD, Benson MD, Buxbaum JN, Ikeda S-I, Merlini G, Saraiva MJM, Westermark P. Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis. Amyloid 2012;19: 167–70. 9. Sipe JD, Benson MD, Buxbaum JN, Ikeda S-I, Merlini G, Saraiva MJM, Westermark P. Amyloid fibril protein nomenclature: 2012 recommendations from the nomenclature committee of the International Society of Amyloidosis. Amyloid 2010;17:101–4. 10. den Dunnen JT, Antonarakis SE. Nomenclature for the description of human sequence variations. Hum Mutat 2000;15:7–12. 11. Maury CPJ. The emerging concept of functional amyloid (review). J Intern Med 2009;265:329–34. 12. Mu¨nch J, Rucker E, Standker L, Adermann K, Goffinet Ch, Schindler M, Wildum S, et al. Semen-derived amyloid fibrils drastically enhance HIV infection. Cell 2007;131: 1059–71. 13. Usmani SM, Zirafi O, Mu¨ller JA, Sandi-Monroy NL, Yadav JK, Meier C, Weil T, et al. Direct visualization of HIV-enhancing endogenous amyloid fibrils in human semen. Nat Commun 2014;5: Article ID:3508. 14. Kalkunte SS, Neubeck S, Norris WE, Cheng SB, Kostadinov S, Vu Hoang D, Ahmed A, et al. Transthyretin is dysregulated in preeclampsia, and its native form prevents the onset of disease in a preclinical mouse model. Am J Pathol 2013;183:1425–36. 15. WHO-IUIS Nomenclature Sub-Committee. Nomenclature of amyloid and amyloidosis. Bull World Health Organ 1993;71:105–12. 16. Benson MD, Liepnicks JJ, Kluve-Beckerman B. Hereditary systemic immunoglobulin light-chain (AL) amyloidosis. XIVth Int Symp Amyloidosis, April 27–May 1, 2014, Indianapolis, IN. 17. Pitka¨nen P, Westermark P, Cornwell III GG. Senile systemic amyloidosis. Am J Path 1984;117:391–9. 18. Westermark P, Sletten K, Johansson B, Cornwell III GG. Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc Natl Acad Sci USA 1990;87:2843–5. 19. D’Souza A, Theis JD, Vrana JA, Dogan A. Pharmaceutical amyloidosis associated with subcutaneous insulin and enfuvirtide administration. Amyloid 2014;21:71–5.
