HUMAN MUTATION Database in Brief 35: E2403–E2412 (2014) Online

HUMAN MUTATION

DATABASE IN BRIEF

Online Registry for Mutations in Hereditary Amyloidosis Including Nomenclature Recommendations

OFFICIAL JOURNAL

www.hgvs.org

Dorota M. Rowczenio1, Islam Noor1, Julian D. Gillmore1, Helen J. Lachmann1, Carol Whelan1, Philip N .Hawkins1, Laura Obici2 , Per Westermark3, Gilles Grateau4 and Ashutosh D Wechalekar1 1Centre

for Amyloidosis and Acute Phase Proteins, University College London Medical School, London, UK; 2 Amyloidosis Research and Treatment Centre, Fondazione IRCCS Policlinico San Matteo Viale Golgi, 19, 27100 Pavia, Italy; 3 Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden; 4 Service de médecine interne, hôpital Tenon assistance publique hôpitaux de Paris université Paris 6 Pierre et Marie Curie, Paris, France *Correspondence to Dorota Rowczenio, Centre for Amyloidosis and Acute Phase Proteins, UCL Medical School, Rowland Hill Street, London NW3 2PF, UK, Email: [email protected] Communicated by Alastair F. Brown

ABSTRACT: Hereditary systemic amyloidosis comprises a group of rare monogenic diseases

inherited in an autosomal dominant fashion. It is associated with mutations in genes encoding eight different proteins, including transthyretin, apolipoprotein AI, apolipoprotein AII, lysozyme, fibrinogen A α-chain, cystatin C, gelsolin and beta-2-microglobulin. With support from the EU FP6 EURAMY project we have designed an online registry of genes and mutations in hereditary amyloidosis including their associated clinical phenotypes, with a view to having a single free online portal for the collection and distribution of this information. Users can search the registry by either mutation, phenotype or authors who have published or submitted mutations. It provides a submission form for reporting newly identified mutations. We also wanted to introduce nomenclature which complies with recommendations set out by Human Genome Variation Society and HUGO Gene Nomenclature Committee for description of new and known genetic variants. We hope this registry would be a useful and convenient tool for the medical and scientific community. ©2014 Wiley-Liss, Inc.

KEY WORDS: Hereditary amyloidosis, online registry, amyloidogenic and non-amyloidogenic mutations

INTRODUCTION Amyloidosis is a rare disorder in which normally soluble proteins undergo a conformational change to generate insoluble, toxic aggregates that are deposited in the extracellular space as abnormal β-sheet fibrils resulting in progressive disruption of the structure and function of affected tissues and organs (Pepys, 2006). Amyloidosis is a Received 3 April 2014; accepted revised manuscript 26 Jun 2014.

© 2014 WILEY-LISS, INC. DOI: 10.1002/humu.22619

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remarkably heterogeneous disease, which can be acquired or hereditary, and systemic or localized. The commonest diagnosed form of systemic amyloidosis is AL amyloidosis, in which the fibrils are derived from monoclonal immunoglobulin light chains and consist of the whole or part of the variable (V L) domain. Hereditary systemic amyloidosis is caused by inheritance of an abnormal gene in an autosomal dominant fashion, which leads to the life-long production of a potentially amyloid forming protein. Eight different fibril proteins have been identified with variant forms which are associated with clinically important familial amyloidosis (Sipe, et al., 2012): transthyretin (ATTR) (Saraiva, et al., 1984; Benson and Uemichi, 1996), apolipoprotein AI (AApoAI) (Nichols, et al., 1988; Rowczenio, et al., 2011), apolipoprotein AII (AApoAII) (Benson, et al., 2001), lysozyme (ALys) (Pepys, et al., 1993; Gillmore, et al., 1999), fibrinogen A α-chain (AFib) (Benson, et al., 1993; Gillmore, et al., 2009), cystatin C (ACys) (Ghiso, et al., 1986), gelsolin (AGel) (Maury, et al., 1992) and beta-2-microglobulin (Aβ2M) (Valleix, et al., 2012) (Table 1). Wider availability of genetic testing, along with recognition that about 5% of cases of systemic amyloidosis are familial, has led to ever increasing numbers of new amyloidogenic and non-amyloidogenic mutations in these genes being identified. We have addressed the clinical and scientific need for a readily accessible repository of mutations and phenotypes in hereditary amyloidosis by creating the first online registry (www.amyloidosismutations.com) with the aim of collecting information on all known variants causing amyloidosis, including their reported clinical phenotype. Another objective was to introduce correct updated nomenclature for describing genetic variants. The current nomenclature used in practice is based on the processed gene product, therefore does not comply with the guidelines set by the Human Genome Variation Society (HGVS; www.hgvs.org/mutnomen) (den Dunnen and Antonarakis, 2000) and HUGO Gene Nomenclature Committee (HGNC). This has become especially important since the introduction of mass spectrometric analysis for fibril typing of amyloid deposits, where use of nomenclature based on the processed protein may result in misclassification of newly identified amyloidogenic protein variants.

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Table 1. Information on genes associated with hereditary systemic amyloidosis and their protein products

Gene Acronym

TTR

Locus

NCBI cDNA Reference Sequence

Gene / Locus MIM No

18q12.1

NM_000371.3

176300

Protein

Fibril Protein Acronym

NCBI Protein Reference Sequence

Transthyretin

ATTR

NP_000362.1

Protein length

Signal Peptide / Propeptide

Mature protein

Amyloidosis Syndrome / Alternative name(s)

Phenotype MIM No

147 AA

20 AA

127 AA

ATTR / Familial Amyloid Polyneuropathy

105210

105200

NONE

107680

Apolipoprotein AI

AApoAI

NP_000030.1

267 AA

18 AA / 6 AA

243 AA

AApoAI / Ostertag Amyloidosis, Nonneuropathic Systemic Amyloidosis

NM_001643.1

107670

Apolipoprotein AII

AApoAII

NP_001634.1

100 AA

18 AA / 5 AA

77 AA

AApoAII

4q31.3

NM_000508.3

134820

Fibrinogen alpha chain

AFib

NP_000499.1

866 AA

19 AA / 16 AA

831 AA

LYZ

12q15

NM_000239.2

153450

Lysozyme

ALys

NP_000230.1

148 AA

18 AA

130 AA

GSN

9q33.2

NM_000177.4

137350

Gelsolin

AGel

NP_000168.1

782 AA

27 AA

755 AA

AGel

105120

B2M

15q21.1

NM_004048.2

109700

Beta-2microglobulin

Aβ2M

NP_004039.1

119 AA

20 AA

99 AA

Aβ2M

105200

CST3

20p11.21

NM_000099.3

604312

Cystatin C

ACys

146 AA

26 AA

120 AA

ACys/ Cerebral Amyloid Angiopathy

105150

APOA1

11q23.3

APOA2

1q23.3

FGA

NM_000039.1

NP_000090.1

AFib / Hereditary Renal Amyloidosis ALys / Hereditary Renal Amyloidosis

105200 105200

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REGISTRY DESIGN The home page of the registry opens with a tabular list of ten buttons. The first eight give access to the disease gene of choice, one for reporting new mutations and the last button providing a link to an online discussion forum (Figure 1).

Figure 1. Home page of the registry showing a tabular list of eight genes. Clicking on any of the genes, leads to further options for accessing the mutations in that particular gene either via the cDNA sequence or in a tabular form.

Specific information on mutations identified in transthyretin (TTR; MIM# 176300), apolipoprotein AI (APOA1; MIM# 107680), apolipoprotein AII (APOA2; MIM# 107670), lysozyme (LYZ; MIM# 153450), fibrinogen α-chain (FGA; MIM# 134820), gelsolin (GSN; MIM# 137350) beta-2-microglobulin (B2M; MIM# 109700) and cystatin C (CST3; MIM# 604312) genes is provided. For each gene, the user can either open a graphical representation of whole or part of the cDNA sequence or a tabular list of mutations with the following information: change at the protein and nucleic acid levels, location of each variant, the type of alteration, the type and number of bases altered, a short description of the known clinical phenotype, ethnicity where the mutation was reported/is common and a link to the Medline citation, if relevant. The citation refers to the first author(s) who identified the mutation(s) either by publication or by personal submission. The distribution of mutations along the cDNA sequence is shown and the user can easily access each variant by simply clicking on the variant name. Hovering the cursor over a variant shows a brief summary of the mutation including the original citation. Clicking the variant name on the cDNA sequence takes the user to specific mutation in the tabular mutation list. The registry has a search facility which provides the user with a quick way to find and extract specific data. This home page has a submit button allowing for submission of novel mutations. There are also links to other web pages providing additional information about each gene including the Online Mendelian Inheritance in Man (OMIM) (http://www.ncbi.nlm.nih.gov/Omim), the genomic, cDNA and protein NCBI reference sequences.

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SOFTWARE AND SEARCH ENGINE The registry was designed using Dreamweaver CS 5.5. The background scripting was done using HTML, JavaScript and PHP. Modification and additions are done locally and then transferred to live server using FTP. Mutation lists are stored on a MySQL database with various tables. The MySQL database is based on Linux platform and has its own control panel, which is accessible via web browser such as Internet Explorer. Any changes and additions of new information are done by the curators. The registry has built-in search engine optimization (SEO) and is searchable by most of the internet search engines. The design of this registry was funded by Sixth European Union framework grant EURAMY (Systemic Amyloidosis in Europe). The registry is maintained by the UK National Amyloidosis Centre. UPDATING NOMENCLATURE The nomenclature currently used by the amyloid community for describing mutations has not followed the general rule of starting with methionine as the translation initiator. As a consequence, almost all amyloidogenic variants described to date have amino acid numbering based on the processed gene product. Since this is not universally recognised and especially as it is not in keeping with current nomenclature recommendations, it has potential to cause serious errors. With the aim to move the amyloidosis gene nomenclature in accordance with current practice, we have designed this registry to include the description that complies with the HGNC and HGVS nomenclature guidelines: cDNA numbering begins at nucleotide 1, which is the A of the ATG translation initiation codon, protein sequence represents the primary translation product and thus includes the signal peptide. For convenience and to avoid confusion, description of protein variants includes both the ‘usual name’ and, in brackets, the nomenclature recommended by HGNC (http://www.genenames.org) and HGVS (http://www.hgvs.org/mutnomen); for example: TTR Val30Met (p.Val50Met); FGA Gly26Arg (p.Gly50Arg); GSN Asp187Asn (p.Asp214Asn). Thus far there is no report of intronic mutations associated with familial amyloidosis. All reference sequences for cDNA and proteins were obtained from the NCBI registry. MUTATION INFORMATION Currently the registry lists 182 variants of genes known to cause hereditary amyloidosis. TTR mutations account for 68%, APOA1 for 13%, FGA for 8%, LYZ for 5%, APOA2 for 2%, GSN for 2%, B2M for 1% and CST3 for 1% (Figure 2).

APOA2 2%

LYZ GSN 5% 2%

B2M CST3 1% 1%

APOA1 13% FGA 8%

TTR 68%

Figure 2. Distribution of mutations in the genes associated with hereditary amyloidosis.

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The vast majority (91%) of reported variants are nonsynonymous point mutations, however frameshifts and deletions also occur. Nine percent of variants have been reported as non-pathogenic or of unknown clinical significance. The ethnic distribution of mutations is very broad and includes German, Portuguese, Swedish, Spanish, Italian, French, Polish, Russian, Japanese, Chinese, British, Irish, African-American, Indian, Finnish, Dutch and other populations. A comprehensive search of the published literature enabled us to gather information about each mutation described to date. In addition, the registry includes 18 novel unpublished mutations (8 in TTR, 4 in APOA1 and 6 in FGA) of these 16 were identified in UK National Amyloidosis Centre and 2 independent submissions to the registry. The details of these mutations and their clinical phenotype are listed in Table 2.

Table 2. 18 unpublished variants identified at the UK National Amyloidosis Centre (16) and due to independent submissions (2), including 4 variants which are either non-pathogenic or of unknown significance Gene

Name (Protein Variant)

Sequence Variant (mRNA)

Codon Change

Location

Reported Phenotype

Ethnic Group

TTR

Phe44Leu (p.Phe64Leu)

c.190T>C

TTT>CTT

Exon 2

H

Caucasian

TTR

Thr49Ser (p.Thr69Ser)

c.206C>G

ACC>AGC

Exon 3

PN

Indian

TTR

Glu54Leu (p.Glu74Leu) Glu54Gln (p.Glu74Gln)

c.220_221delinsTT

GAG>TTG

Exon 3

H

Belgian

c.220G>C

GAG>CAG

Exon 3

H, PN

Romanian

Glu72Gly (p.Glu92Gly) Ala81Val (p.Ala101Val) His90Asp (p.His110Asp)

c.275A>G

GAA >GGA

Exon 3

H

Caucasian

c.302C>T

GCA>GTA

Exon 3

H

c.328C>G

CAT>GAT

Exon 3

H

Russian, Polish British

TTR

Ile107Phe (p.Ile127Phe)

c.379A>T

ATT>TTT

Exon 4

AN, PN

British

APOA1

Gly35Val (p.Gly59Val)

GGC>GTC

Exon 3

Caucasian

APOA1

Trp50Arg (p.Trp74Arg)

c.220T>A

TGG>AGG

Exon 4

APOA1

Ala164Ser (p.Ala188Ser)

c.562G>T

GCC>TCC

Exon 4

APOA1

Gln172Pro (p.Gln196Pro) Phe521Serfs*27 (p.Phe540Serfs*27)

c.587_588delinsCC

CAG>CCC

Exon 4

c.1619_1622delTTGT

5' end of exon5

Glu524Lys (p.Glu543Lys) Glu526Lys (p.Glu545Lys)

c.1627G>A

Frame shifting mutation GAG>AAG

Unknown significance Renal impairment Unknown significance Likely amyloidogenic Renal failure

Renal failure

Caucasian

c.1633G>A

GAG>AAG

Renal failure

Russian

Gly555Phe (p.Gly574Phe) Gly519Arg (p.Gly538Arg)

c.1720_1721delinsTT

GGT>TTT

Renal failure

Norwegian

c.1612G>A

GGA>AGA

British

Gly519Glu (p.Gly538Glu)

c.1613G>A

GGA>GAA

non-pathogenic/ unknown significance non-pathogenic/ unknown significance

TTR TTR TTR TTR

FGA

FGA FGA FGA FGA

FGA

c.176G>T

5' end of exon5 5' end of exon5 5' end of exon5 5' end of exon5 5' end of exon5

Danish Caucasian Caucasian Arab

British

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SUBMISSION OF NEW MUTATIONS AND ONLINE DISCUSSION FORUM Submission of new mutation to the registry is available via a button on the home page or from any of the genes. Selecting this button leads to an online submission form which consists of the following fields: author(s) name and email address, name and number of change at protein and cDNA level, location of mutation, phenotype and patient’s ethnicity. On the form, next to each box, there is an example on how the data should be entered on the form (Figure 3). Additionally, by ticking the relevant box(s) on this form authors would have to specify method used to detect amyloid deposit. A new mutation would be considered pathogenic if there would be sufficient clinical information provided by the author, histological evidence of amyloid deposition and appropriate amyloid fibril type was confirmed by IHC and/or LMD/MS. On submission, the form is directed to the curators who review the information and add it to the registry. This should permit faster and more efficient collection of appropriate information. All mutations submitted will be referenced to the submitting author and/or the appropriate Medline citation if available.

Figure 3. The form for submission of new mutations. Mutations submitted will be reviewed by the curators and added to the registry.

The registry also includes an online discussion forum which the curators hope will be a portal for discussion by and for the amyloidosis genetic community as well as a mechanism for anyone to communicate with the curators of the registry. DISCUSSION Hereditary amyloidosis is an autosomal dominant disease with a variable penetrance. Most affected individuals are heterozygous although rare homozygous cases have been reported (Holmgren, et al., 1992; Yoshinaga, et al., 1994). Hereditary amyloidosis can clinically present form early childhood upwards, but is usually a late-onset disease. Hereditary transthyretin (ATTR) amyloidosis is the commonest and has greatest genetic variability. More

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than 120 amyloidogenic TTR mutations have been described. ATTR amyloidosis usually presents with peripheral and autonomic neuropathy, but can also present as cardiac amyloidosis (Saraiva, 2002; Connors, et al., 2003; Koike, et al., 2009). The TTR V122I variant is present in about 4% of the Afro-Caribbean population and is associated with late onset cardiac amyloidosis in an undetermined proportion of cases (Jacobson, et al., 1997). Hereditary non-neuropathic systemic amyloidosis (Ostertag, 1932) is associated with mutations in the APOA1 (Jones, et al., 1991; Soutar, et al., 1992; Booth, et al., 1995; Persey, et al., 1998; Hamidi Asl, et al., 1999; Obici, et al., 1999; de Sousa, et al., 2000; Murphy, et al., 2004; Rowczenio, et al., 2011), APOA2 (Benson, et al., 2001), LYZ (Pepys, et al., 1993) and FGA (Benson, et al., 1993; Uemichi, et al., 1994; Hamidi Asl, et al., 1997; Gillmore, et al., 2009) genes. The clinical amyloidosis syndromes caused by the various mutations are remarkably diverse with respect to age of onset, mode of presentation, pattern of organ distribution, rate of progression, and prognosis. Renal involvement occurs with most mutations; however amyloid deposition can affect any or all of the major viscera. Apolipoprotein AI amyloidosis can occasionally present with neuropathy (Hazenberg, et al., 2009; Nichols, et al., 1990). Whilst the most commonly identified variants are well documented with good information on the clinical phenotype and natural history, information on rarer variants including their amyloidogenic potential is difficult to obtain. Clinical significance of new mutations is often unclear due to lack of family history, reduced penetrance and other factors. Prior to the creation of this registry, there was no central repository containing detailed information. Small databases for individual gene mutations have been available but information on mutations in this disease generally was scattered. The idea to create an online registry of mutations in hereditary amyloidosis and associated clinical phenotypes was first proposed at the EU FP6 EURAMY meeting in 2007 and the UK National Amyloidosis Centre was put in charge of this project. First, we gathered information on mutations reported in each gene by comprehensive search of the published literature. In 2010, we centralized this data by establishing the registry and search tool, at www.amyloidosismutations.com, with the aim to make it easily accessible to the scientific and medical communities. Since its launch the website has been regularly updated with new variants identified from publications or those identified in our own centre. Since the start in 2010, a total of 47 new mutations (including the 18 mutations listed in Table 2), have been added to the registry. Correct mutation nomenclature is essential. Compliance with the HGNC and HGVS nomenclature guidelines in the registry gives access to both “common” and correct gene nomenclature. This will allow researchers to have a uniform platform for efficient designing of tests and accurate reporting, and should ideally be used in all diagnostic laboratories. We hope this will prevent future confusion in describing genetic variants in this disease. The ability to submit new mutations online provides an efficient method for collecting and disseminating information. Currently, the registry contains 182 sequence variants in related genes; we hope that this number will increase in the future as we encourage clinicians and geneticist to collaborate in submission of novel variants to this registry. Routine use by the entire amyloidosis community will allow this resource to eventually help accurate documentation of genotype/phenotype correlations. In summary, we report the first registry of mutations in hereditary amyloidosis as a free online resource for the clinical and scientific community for accessing information about and reporting new mutations and phenotypes in hereditary amyloidosis. ACKNOWLEDGMENTS This work was supported by the EU FP6 EURAMY project; Work package 3. REFERENCES Benson MD, Liepnieks J, Uemichi T, Wheeler G, Correa R. 1993. Hereditary renal amyloidosis associated with a mutant fibrinogen a-chain. Nature Genetics 3:252-255. Benson MD, Liepnieks JJ, Yazaki M, Yamashita T, Hamidi Asl K, Guenther B, Kluve-Beckerman B. 2001. A new human hereditary amyloidosis: the result of a stop-codon mutation in the apolipoprotein AII gene. Genomics 72:272-277. Benson MD, Uemichi T. 1996. Transthyretin amyloidosis. Amyloid: Int. J. Exp. Clin. Invest. 3:44-56.

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Booth DR, Tan SY, Booth SE, Hsuan JJ, Totty NF, Nguyen O, Hutton T, Vigushin DM, Tennent GA, Hutchinson WL and others. 1995. A new apolipoprotein AI variant, Trp50Arg, causes hereditary amyloidosis. Q.J. Med. 88:695-702. Connors LH, Lim A, Prokaeva T, Roskens VA, Costello CE. 2003. Tabulation of human transthyretin (TTR) variants, 2003. Amyloid 10:160-184. de Sousa MM, Vital C, Ostler D, Fernandes R, Pouget-Abadie J, Carles D, Saraiva MJ. 2000. Apolipoprotein AI and transthyretin as components of amyloid fibrils in a kindred with apoAI Leu178His amyloidosis. Am. J. Pathol. 156:19111917. Ghiso J, Jensson O, Frangione B. 1986. Amyloid fibrils in hereditary cerebral hemorrhage with amyloidosis of Icelandic type is a variant of g-trace basic protein (cystatin C). Proc. Natl. Acad. Sci. USA 83:2974-2978. Gillmore JD, Booth DR, Madhoo S, Pepys MB, Hawkins PN. 1999. Hereditary renal amyloidosis associated with variant lysozyme in a large English family. Nephrol. Dial. Transplant. 14:2639-2644. Gillmore JD, Lachmann HJ, Rowczenio D, Gilbertson JA, Zeng CH, Liu ZH, Li LS, Wechalekar A, Hawkins PN. 2009. Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis. J. Am. Soc. Nephrol. 20:444-451. Hamidi Asl L, Liepnieks JJ, Hamidi Asl K, Uemichi T, Moulin G, Desjoyaux E, Loire R, Delpech M, Grateau G, Benson MD. 1999. Hereditary amyloid cardiomyopathy caused by a variant apolipoprotein A1. Am. J. Pathol. 154:221-227. Hamidi Asl L, Liepnieks JJ, Uemichi T, Rebibou JM, Justrabo E, Droz D, Mousson C, Chalopin JM, Benson MD, Delpech M and others. 1997. Renal amyloidosis with a frame shift mutation in fibrinogen a a-chain gene producing a novel amyloid protein. Blood 90:4799-4805. Hazenberg AJ, Dikkers FG, Hawkins PN, Bijzet J, Rowczenio D, Gilbertson J, Posthumus MD, Leijsma MK, Hazenberg BP. 2009. Laryngeal presentation of systemic apolipoprotein A-I-derived amyloidosis. The Laryngoscope 119:608-615. Holmgren G, Bergström S, Drugge U, Lundgren E, Nording-Sikström C, Sandgren O, Steen L. 1992. Homozygosity for the transthyretin-Met-30-gene in seven individuals with familial amyloidosis with polyneuropathy detected by restriction enzyme analysis of amplified genomic DNA sequences. Clin. Genet. 41:39-41. Jacobson DR, Pastore RD, Yaghoubian R, Kane I, Gallo G, Buck FS, Buxbaum JN. 1997. Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N. Engl. J. Med. 336:466-473. Jones LA, Harding JA, Cohen AS, Skinner M. 1991. New USA family has apolipoprotein AI (Arg26) variant. In: Natvig JB, Førre Ø, Husby G, Husebekk A, Skogen B, Sletten K, Westermark P, editors. Amyloid and Amyloidosis 1990. Dordrecht: Kluwer Academic Publishers. p 385-388. Koike H, Ando Y, Ueda M, Kawagashira Y, Iijima M, Fujitake J, Hayashi M, Yamamoto M, Mukai E, Nakamura T and others. 2009. Distinct characteristics of amyloid deposits in early- and late-onset transthyretin Val30Met familial amyloid polyneuropathy. J. Neurol. Sci. 287:178-184. Maury CP, Kere J, Tolvanen R, de la Chapelle A. 1992. Homozygosity for the Asn187 gelsolin mutation in Finnish-type familial amyloidosis is associated with severe renal disease. Genomics 13:902-903. Murphy CL, Wang S, Weaver K, Gertz MA, Weiss DT, Solomon A. 2004. Renal apolipoprotein A-I amyloidosis associated with a novel mutant Leu64Pro. Am. J. Kidney Dis. 44:1103-1109. Nichols WC, Dwulet FE, Liepnieks J, Benson MD. 1988. Variant apolipoprotein AI as a major constituent of a human hereditary amyloid. Biochem. Biophys. Res. Commun. 156:762-768. Nichols WC, Gregg RE, Brewer HBJ, Benson MD. 1990. A mutation in apolipoprotein A-I in the Iowa type of familial amyloidotic polyneuropathy. Genomics 8:318-323. Obici L, Bellotti V, Mangione P, Stoppini M, Arbustini E, Verga L, Zorzoli I, Anesi E, Zanotti G, Campana C and others. 1999. 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. Am. J. Pathol. 155:695-702. Ostertag B. 1932. Demonstration einer eigenartigen familiaren paraamyloidose. Zentralbl. Aug. Pathol. 56:253-254. Pepys MB. 2006. Amyloidosis. Annu. Rev. Med. 57:223-241.

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Pepys MB, Hawkins PN, Booth DR, Vigushin DM, Tennent GA, Soutar AK, Totty N, Nguyen O, Blake CCF, Terry CJ and others. 1993. Human lysozyme gene mutations cause hereditary systemic amyloidosis. Nature 362:553-557. Persey MR, Booth DR, Booth SE, van Zyl-Smit R, Adams BK, Fattaar AB, Tennent GA, Hawkins PN, Pepys MB. 1998. Hereditary nephropathic systemic amyloidosis caused by a novel variant apolipoprotein A-I. Kidney Int. 53:276-281. Rowczenio D, Dogan A, Theis JD, Vrana JA, Lachmann HJ, Wechalekar AD, Gilbertson JA, Hunt T, Gibbs SD, Sattianayagam PT and others. 2011. Amyloidogenicity and Clinical Phenotype Associated with Five Novel Mutations in Apolipoprotein A-I. Am. J. Pathol. 179:1978 - 1987. Saraiva MJ. 2002. Hereditary transthyretin amyloidosis: molecular basis and therapeutical strategies. Expert Rev. Mol. Med. 2002:1-11. Saraiva MJM, Birken S, Costa PP, Goodman DS. 1984. Amyloid fibril protein in familial amyloid polyneuropathy, Portuguese type. Definition of molecular abnormality in transthyretin (prealbumin). J. Clin. Invest. 74:104-119. Sipe JD, Benson MD, Buxbaum JN, Ikeda S, Merlini G, Saraiva MJ, Westermark P. 2012. Amyloid fibril protein nomenclature: 2012 recommendations from the Nomenclature Committee of the International Society of Amyloidosis. Amyloid 19:167-170. Soutar AK, Hawkins PN, Vigushin DM, Tennent GA, Booth SE, Hutton T, Nguyen O, Totty NF, Feest TG, Hsuan JJ and others. 1992. Apolipoprotein AI mutation Arg-60 causes autosomal dominant amyloidosis. Proc. Natl. Acad. Sci. USA 89:7389-7393. Uemichi T, Liepnieks JJ, Benson MD. 1994. Hereditary renal amyloidosis with a novel variant fibrinogen. J. Clin. Invest. 93:731-736. Valleix S, Gillmore JD, Bridoux F, Mangione PP, Dogan A, Nedelec B, Boimard M, Touchard G, Goujon JM, Lacombe C and others. 2012. Hereditary systemic amyloidosis due to Asp76Asn variant beta2-microglobulin. N. Engl. J. Med. 366:22762283. Yoshinaga T, Nakazato M, Ikeda S, Ohnishi A. 1994. [Three siblings homozygous for the transthyretin-Met30 gene in familial amyloidotic polyneuropathy--evaluation of their clinical pictures with reference to those of other 10 cases reported]. Rinsho Shinkeigaku 34:99-105.

Online registry for mutations in hereditary amyloidosis including nomenclature recommendations.

Hereditary systemic amyloidosis comprises a group of rare monogenic diseases inherited in an autosomal dominant fashion. It is associated with mutatio...
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