Prot Fold Dis2

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Familial Amyloidotic Polyneuropathy Familial Amyloidotic Polyneuropathy

FAP in a nutshell

Severe peripheral neuropathy

Late onset

Familial Systemic deposition of amyloid

• Sensitive and autonomic, and later also motor dysfunction. motor dysfunction. • Simetrical, centripetal and progressive.

• mean age at onset 35 yrs.

• Autosomal dominant.

• Vascular walls, peripheral nerves, thyroid,  kidney, etc. • CNS and liver spared.

Corino Andrade

FAP ‐ Genetics Familial, autosomic , dominant.

No modifier genes identified so far, but familial  aggregation of subphenotypes.

Parent of origin effects: Anticipation of age at  onset, increased penetrance, particularly on  mother to child transmission. Still unexplained  (genetic imprinting?). (g p g )

I II

III IV

?

FAP ‐ Pathology gy Generalized deposition of amyloid, with predisposition for small arteriolar walls,  peripheral nerves, thyroid, kidney, etc.

CNS and liver spared.

Kidney

Severe loss of axonal fibers in later stages of the disease Peripheral nerve

II – Molecular Biology

FAP – Molecular Biology FAP  Molecular Biology The fundamental constituent of amyloid in PAF is identical immunochemically to a small serum protein, transthyretin (TTR). [Costa et al., PNAS, 1978]

Bi h i l characterization Biochemical h t i ti off this thi fundamental constituent of amyloid reveals the presence of a TTR mutation,  with ith a methionine thi i for valine f li substitution at position 30. [Saraiva et al., Trans Assoc Am Physicians, 1983]

FAP ATTR V30M

-20 -10 ACAGAAGTCCACTCATTCTTGGCAGGATGGCTTCTCATCGTCTGCTCCTCCTCTGCCTTGCTGGA ..........................-M--A--S--H--R--L--L--L--L--C--L--A--G-1 1 10 CTGGTATTTGTGTCTGAGGCTGGCCCTACGGGCACCGGTGAATCCAAGTGTCCTCTGATGGTCAAA -L--V--F--V--S--E--A--G--P--T--G--T--G--E--S--K--C--P--L--M--V--K20 30 GTTCTAGATGCTGTCCGAGGCAGTCCTGCCATCAATGTGGCCATGCATGTGTTCAGAAAGGCTGCT -V--L--D--A--V--R--G--S--P--A--I--N--V--A--M--H--V--F--R--K--A--A40 50 GATGACACCTGGGAGCCATTTGCCTCTGGGAAAACCAGTGAGTCTGGAGAGCTGCATGGGCTCACA -D--D--T--W--E--P--F--A--S--G--K--T--S--E--S--G--E--L--H--G--L--T60 70 80 ACTGAGGAGGAATTTGTAGAAGGGATATACAAAGTGGAAATAGACACCAAATCTTACTGGAAGGCA -T--E--E--E--F--V--E--G--I--Y--K--V--E--I--D--T--K--S--Y--W--K--A90 100 CTTGGCATCTCCCCATTCCATGAGCATGCAGAGGTGGTATTCACAGCCAACGACTCCGGCCCCCGC -L--G--I--S--P--F--H--E--H--A--E--V--V--F--T--A--N--D--S--G--P--RG S S G 110 120 CGCTACACCATTGCCGCCCTGCTGAGCCCCTACTCCTATTCCACCACGGCTGTCGTCACCAATCCC -R--Y--T--I--A--A--L--L--S--P--Y--S--Y--S--T--T--A--V--V--T--N--P127 AAGGAATGAGGGACTTCTCCTCCAGTGGACCTGAAGGACGAGGGATGGGATTTCATGTAACCAAGA -K--E--*-......................................................... GTATTCCATTTTTACTAAAGCAGTGTTTTCACCTCATATGCTATGTTAGAAGTCCAGGCAGAGACA ..................................................................

Chr 18 Chr.

ATAAAACATTCCTGTGAAAGGCACTTTTCATTCC ..................................

Amyloid Type

Precursor

Disease

AA

apoSAA SAA

SSecondary (reactive) amyloidosis d ( ti ) l id i FMF

AL

Ig light chains (κ,λ)

ATTR

Transthyretin TTR V30M TTR L111M

Senile systemic amyloidosis Polyneuropathy Cardiomiopathy

AapoAI

apoA‐I Arg 26 apoA‐I Arg 60

Polyneuropathy, Nephropathy Nephropathy

A Lys

Lysozime Thr 56, His 67

Nephropathy

AFibA

Fibrinogen Aα E526V, R554L

Nephropathy

AGel

Gelsolin Asn 187

FFA

ACys

Cystatin C Gln 68

HCHWA, Icelandic type

Aβ2M

β2‐microglobulin

Hemodialisis amyloidosis



βPP βPP Gln 618

Alzheimer s disease Alzheimer’s disease HCHWA, Dutch type

AScr

PrPC, PrPSc, PrPCJD

Kuru, Scrapie, CJD, GSS

AIAPP

A ili Amilin

Di b Diabetes melitus, type 2 li 2

ACal

procalcitonin

Thyroid medulary carcinoma

TTR M t ti TTR Mutations Neuropathy Arg 47 Glu 18 Leu 30 Leu 33 Asn 35

Vitreous/other

Ile 50

Gly 54 Gly 54

Tyr 77

Val 107

Lys 61

Val 33

Gly 42

Ala 30 Ser 24 Thr 34 Gln 89 Ala 47

Arg 58

Cys 114 Ile 33 Ile 33 Ala 49

Pro 36 Pro 36 Val 47

Ile 50 Thr 45 Thr 45

Cardiomiopathy

Gly 18 Gly 30

Met 30

Ala 60 Pro 55 Arg 10 His 69 His 69 Ile 112 Ala 71 Arg 50 Leu 64 Ile 122 Lys 59 Ser 84 Gly 97 Asp 45 Leu 68 Ile 20

P 12 Pro 12

His 60

Met 111 Ser 125

Ser 6 Met 119

III – Epidemiology

FAP Epidemiolgy FAP ‐ 3525 TTR V30M carriers registered at Centro de Estudos de  Paramiloidose, Porto (June 2008),  covering i most patients i and d heathy h h carriers above 20 years of age  (data from genetic counceling).

The residence of 97% of these carriers is known. Northern coastal areas most heavily affected.

Number of live patients > 1000.  g y p National registry implementation under way.

PAF ‐ distribuição d de portadores / nut3 t d / t3 100 ou mais (4) 60 a  99 (3) 40 a  59 (3) 30 a  39 (3) 20 a  a 29 (2) 10 a  19 (2) 0 a  9 (11)

Cávado (733) Grande Porto G d P (1206)

Junho de 2008 

Baixo Vouga (102) Baixo Mondego (261)

Grande Lisboa G d Li b (291) Península de Setubal (90)

Serra da Estrela (78) (72) Cova da Beira

FAP Prevalence Studies FAP ‐ Prevalence Studies Northern Portugal, one study only (HIEF) Alves IL et al. Human Mutation 1997, 9(3), 226‐33 , ( ),

In 5000 individuals: • • • • • • •

Met 30 Met 119 Met 30/Met 119 Asn 90 Ile 122 Unknown Thr 190

8 35 1 12 1 3 1

FAP Prevalence Studies FAP ‐ Prevalence Studies

Northern Sweden – endemic counties (ELISA) Holmgren et al. J Med Genet 1994, 31, 351‐4

In 1276 individuals: • Met 30 16 • Met 30/Met 30 3 • Other mutations not looked for

FAP – World Distribution FAP 

© 2001 National Geographic Society

The Travels of a Gene?

© 2001 National Geographic Society

III - Diagnosis

Histopathology Biopsies • Nerve and skin • Fat aspirate p • Other

The basis of diagnosis in old times (before genetic testing) It is rarely positive in asymptomatic carriers

ATTR V30M – Molecular Testingg 30 ·· AGTCCTGCCATCAATGTGGCCGTGCATGTG ·· ·· -S--P--A--I--N--V--A--V--H--V- ··

↓ ·· AGTCCTGCCATCAATGTGGCCATGCATGTG ·· ·· -S--P--A--I--N--V--A--M--H--V- ··

ATTR Diagnosis – DNA Sequencing ATTR Diagnosis  DNA Sequencing

Alternatives

TTR V28M

• SSCP • DHPLC • etc. t

IV - Treatment

FAP - Treatment ea e Before the advent of liver transplantation, FAP was an incurable disease.

Liver transplantation is a primitive a primitive form of gene therapy,  gene therapy and is effective because > 90% of human TTR is produced in the liver.

Only current alternative: Prevention [PND, DGPI] [PND DGPI]

PAF – Prevenção Primária PAF  Prevenção Primária ƒ Aconselhamento genético • Diagnóstico pré‐natal

• Diagnóstico pré‐implantação g p p ç

DESENVOLVIMENTO EMBRIONÁRIO PRÉ-IMPLANTAÇÃO É

1º Dia

Dia 1-2

Dia 2

Dia 3



1º e 2º glóbulos polares



1 a 2 bl blastómeros, ó ao 3º di dia



Células da trofoectoderme de blastocistos, ao 5º dia

BIÓPSIA

Dia 4

Dia 5

Dia 6-7

Dia 6

PROCESSO DE FIV • Exames preliminares ♀ ♂ • Estimulação: ≥ 9 ovócitos • ICSI - não contaminação

ez células él l s d da granulosa l s

ABERTURA DA ZONA PELÚCIDA • Solução ácida de Tyrode (pH 2.2) • Laser • Dissecção parcial

*Meio sem Ca2+/Mg2+

TRANSFERÊNCIA DE EMBRIÕES 4º ou 5º dia após punção folicular

TAXA DE GRAVIDEZ CLÍNICA EM DGPI 22,4%

Prevenção Secundária Prevenção Secundária • Inibição da formação de amilóide • Esta Estabilizadores za or s do o ttetrâmero trâm ro de TTR • Remoção da proteína circulante

• Remoção dos depósitos • Antagonistas dos glicosaminoglicanos

Fib il é Fibrilogénese ‐ I Estudos realizados in vitro com proteínas purificadas. purificadas

Estes estudos mostraram que é relativamente fácil q obter fibras com as características genéricas das fibras de amilóide a partir de um grande número de proteínas ou fragmentos proteicos.

Fib il é Fibrilogénese ‐ II A fibrilogénese passa quase sempre pela formação de um intermediário, que pode formar fibras de imediato, ou a partir de agregados de tipo amorfo.

ATTR - Fibrilogenesis

Native tetramer

pH <3

pH 3

pH 5.3

Rearranjed tetramer

Early model, based on acidic denaturation

A-state

Amyloid fibrils

SAP

GAGs

Serag et al. Nature Struct Biol 9: 734-9, 2002

ATTR Citotoxicity Mechanisms ATTR ‐ Citotoxicity Mechanisms

Hou, X. et al. FEBS Journal 2007, 274 (7), 1637-50.

Kadowaki et al., J Chem Neuroanatomy 28 (2004) 93–100

FAP – C Clinical ca Trials as

DMSO

CEP

II/III (?)

1984

Apheresis

CEP

I/II

2001

CPHPC (Ro 63‐8695)

CAAPP / Roche

II/III

2002

Fx‐1006A

FoldRx

II/III

2009

Difl i l Diflunisal

BUMC

II/III

2010

Doxycyclin

IBMC

?

?

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