Hereditariedade - ASIC · Hereditariedade!!!!! Influenciada pelo sexo"! x˝ o l dfr. # ) ˇ Vf ˙ o...
Transcript of Hereditariedade - ASIC · Hereditariedade!!!!! Influenciada pelo sexo"! x˝ o l dfr. # ) ˇ Vf ˙ o...
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Hereditariedade ���������������������
não Mendeliana �t �) � ada5�N � h� )p mt vf �M a): U�
� � o � ra� � f �� � � ad…………�
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ü � � � � Vaf r� e� � r � � � o f d� � vd� r �à � pa� r � o f d� � vd� V� r � � f o l d� x� r �
ü � � � � evd� � � f � e� � n � � � � � � l ae� � n� � �
ü � � � � � gf V� r � � o � a� g� ar� � � � rgf � � rn� f r2 � �
5M � f f e� a� � � � f �o � � � da� � �
HM Dv � � a� � � � l � df � r � xf �
6M � vg� � c � r � � a � o a� � r �
7M o l Va n e� e� � n � f �
/M � V� � ag� Va� � � � � �o agf � f � Va� d�
EM � V� � ag� Va� � � � � �� ae� a� � �
: M � V� � ag� Va� � � � � �o vdn� � � gf Va� dI �� f o l d� x� �
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Hereditariedade���������������������
Influenciada pelo sexo
ü � x� o l df r.� ��
§ � � � Vf � � � � o � o � I f p� Vaf � � � o vg� � c � r � f r� e� � r � � � � � 5� � � � � � � H�
§ � v � � V� � � � � l V� � f � � � � � o vg� � � f � f � V� � � l gf V� � � 3� � õ��
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Mutações���������������������
Dinâmicas
ü Ocorrem em regiões repetitivas do DNA (repetição em tandem de número variável)
ü As repetição em tandem constituem uma fração considerável do genoma de muitos organismos eucarióticos
ü A expansão número de repetições pode ocorrer devido a instabilidade mitótica
ü A expansão não afecta o fenótipo, até um certo número de unidades repetitivas, denominando-se esta fase de pré-mutação. A partir de um certo tamanho, observa-se um efeito patogénico.
ü O nº de unidades repetitivas não se mantém constante transgeneracionalmente, podendo diminuir ou aumentar. p �c ap � aN� � mfa�f af � b� � t fU�� da� � a: a�U � � 2: �t fm t N� � a� h�t mfp f � �t � � p p t � � omt � m: daf � >TTZ�
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Anomalias conformacionais
da proteina
� dMfUo�� � � b o� � p md0� � �o df t � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� � � � � � � � � � � � � � � � � � � � )�
Doença de Huntington-HTT Doença de Huntington-HTTTTTTTT
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Quanto maior a expansão, mais graves e precoces serão os sintomas
Fisiopatologia na doença de Huntington Fisiopatttologia na doença de Huntington
Agregação nuclear
Repressão da transcrição Agregação
citoplasmática
Disfunção da endocitose
Toxicidade mitocondrial
Disfunção do transporte
Inclusões perinucleares
Conformação anormal
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✓ � V� p� d� � a� .� 5� � o � H41444� � � � � g� � f r �
✓ � V� ! v � R� � o vr� vd� V� � � o af gf a� � l Vf eV� rrap� rM� �
✓ � f � � � � � � � g� V� f vgVf r� f Ve� f r.� f dmf r1� � f V� � � f � � �� � V� � Vf M� �
✓ � xl V� rrapa� � � � � p� Va� p� dM�
✓ � � a� � � � � � � � a s� af � � � o � ar� l V� � f � � � � � f r � rs gf o � r � o � ar�eV� p� r � � � o � � a� � � ! v � � f � ç� � � � V� l � n � c � r � � vo � g� � �
Distrofia miotónica - DMPK Distrofia miotóóóóónica - DMPK
DMPK DMPK
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X- Frágil X- Frágil
FRAXA FRAXAAA
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�
º � � � cat a� � � � � � � me� �� : �o �� � � � � � � õbo�c mda� � �p at U�d � oaU�o �R t � : o Uamt G)�
º � � p � o�� afU�� : o Uait �� fas�� at � t Uo� �� ap �U �f � �f � t f f �f � � ndMd�f (� n� p �mf � �� Mt �t Ua� t �f �� ndMd�f � t aoP f �f �à� t �f � at omUaf)�
� Mp at U � � t ç� a� oa: aR� gaf � � � � �
� � a2� aff � a� p � � � a� � � � S � � p �
: oap MU�� � � n� UI 2m� �: �o �� �� � ndMd��
t aMo t �d �à� � � � � � � �
w>TT� oa: aR� gaf �à�hm: aop aRd�� � � �cat a�à� � Mf. t � m�� a� � � � S �à� v� o�c md�
�
� t �� � mt 5at U�� � onvp MU�� � �ZZv>TT� � � � �
� MU�� � � � p : daU��w>TT� � � � �
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DOENÇAS EM REGIÕES ���������������������
SUJEITAS A IMPRINTING
� me� �� gaf � a: mcat nR� �f � � t M5ap � �� Mp �� a2: oaff � � cat nR� �� mbaoat � m�d � a� �� o � � p � �� fM�� omcap � : �o at U�d )�
IMPRINTING IMPRINTING
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IMPRINTING – genes expressos dependendo da origem parental IMPRINTING – genes expressos dependendo da origem parentaaal
Alelo paterno
Alelo materno
� d� df rI � � � � r � rad� � a� � f r � � � l � � � � f � � � � rv � � f Vae� o � l � V� g� d� l f V� o � nd� � � f �� m� � � Mp � coM: � p aRd � �� � mU fmt �� a� mt M� daI R f � �: � � af : a� ie� f (� mt m� mt � �� a2: oaff � � f � cat af � ap � DMafU� � õ� io� Md � afp aRd�� � � oap aRd�� � � admp mt �� mp : omt Rt c� : onPm � a� oavafU�� ada� a� � t P � mp : omt Rt c� af: a� ie� � �� j t P�é � omcap � : �o at U�d G�
� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �
� � � �� � � � � � � � � � � � � � � � � � �� � � � � � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � i � � � � � � � � � � �� � � � � � � � �� � � � � � � � � � � � � � � � � � � � �� � ã � � � � � �� � � � � � � � � �� � � � � � � � � � �� � � � � � � � �� � � � � � � � � � � � � � � � � � � � � � ç� � � �� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �� “ � � � � ” � � � � � � � � � �� � � � �� o�
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Dissomia uniparental Dissomia uniparentaaal
Dissomia uniparental Dissomia uniparentaaal
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2
1 X
Dissomia uniparental – como acontece Dissomia uniparentaaal – como acontece
3
4
X
1/3 rescue errado!!
Dissomia uniparental – como acontece Dissomia uniparentaaal – como acontece
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� � � � � � mff p m�� � t m: �o at U�d � : a�p �t mbafU�o vfa� � dmt m� � p at Ua� aPm � � N�
�
• p 5mc R�� : �o �� �d ad f � oa� affmP �õ�: at �f � mf mff p m�G X� �
• � ba� U�o � oacmgaf � fMsamU�f � �� mp : omt Rt c)� �
Dissomia uniparental Dissomia uniparentaaal
Phenotype – Syndromes involving imprinted genes Chromosomal location
� a� ur mUhA� ma ap � t t � f0t o p a� � SS: SZ� p �U �õ>T; � � � � � : �U � X� SZ; � � � G�
� o� aoA� mddm� f0t o p a� � SZDSSvDS>� : �U �õ� >Z; � � � � � p �U X� qZ; � adG�
� t cadp �t � f0t o p a� �SZDSSvDS>� p �U �
õêvZ; � � � � � : �U X� qT; � adX� �STvSZ; � p MU� � � � ê� G�
� mdPaoA� Mffadd� f0t o p a� � SS: SZ� : �U �
� o�t fmat U� t a t �U �d � m�� aUaf � p addmUMf � � àD>á� p � U�
� � p mdm�d � t t � ho p �l t � : �o �c �t cdm p �� � SSDSê� �
� �U aot �d � �t � : �U aot �d � � � � Sá� f0t o p af � � Sá� �
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Angelman/ Prader-Willi Angelman/ Prader-Willi
Síndrome Prader-Willi Síndrome Prader-Willi
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� M� o � � dit m� �
v� � � � � � � � �
v m: U t m�� co� Pa� õz � � m a5G�v � me� Md � af � �d mp at U�o af �
v� � � � � � afm � a�
v m: c t � mfp �
v � �mf � U� o aN� � � � � � � � � � � � X� � afm � a�
Síndrome Prader-Willi Síndrome Prader-Willi
Síndrome Prader-Willi Síndrome Prader-Willi
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Síndrome angelman Síndrome angelman
§ � � � � � õdmt cM�c ap G�
§ � o � dap �f � a� � o at �� � � f � p Pmp at U � a� aDMmdi� om X��U �2 m� (� Uoap oí �
§ � : mda: fm��
§ � Uo�f � t � � oaf � mp at U � � : aoip aUo � � ab�d m� � ap � “T; � f �� � f f (� � ooat � p m� o � ab�d m�� : ad f � >� �t f � a� m � a)�
§ � oaDMat Ua� DM�d DMao� � p � mt �� � � a� omf � a� f oomf (� � p �Mp �� �: �o . t � m�� badm5
Síndrome angelman Síndrome angelman
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Síndrome angelman Síndrome angelman
Beckwith-Wiedemann/ Silver-Russell Beckwith-Wiedemann/ Silver-Russell
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Síndrome de Beckwith-Wiedemann Síndrome de Beckwith-Wiedemann
ü � � oav� oaf � mp at U � cat ao�d m5� � a, M� d � �d m5� � ap � oa� np � t �f � m f )� �
ü >T; � mff p m�� Mt m: � oat U�d � : �U aot �� a� SS: SZ�
Síndrome Beckwith-Wiedemann Síndrome Beckwith-Wiedemann
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Síndrome Beckwith-Wiedemann Síndrome Beckwith-Wiedemann
Síndrome de Silver-Russel Síndrome de Silver-Russel
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Síndrome Silver-Russel Síndrome Silver-Russel
Síndrome Silver-Russell Síndrome Silver-Russell
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� f ra� � V� � c � r � � ds a� � r.��
5)� � o p ff p �f � � p � p �m o� oadaP�t � m�� � dit m� �N � à(� q(� SS(Sá� a� SZ)��HM� � afUa� �� � � � � aPa� fao� � p fm ao� �� ap N�
õ� G � mUM�� gaf � a� p f �m� mfp � M� Uo�t fd � �� gaf � o � aoUf t m�t �f � : �o �� f � � o p ff p �f �� dmt m� �p at Ua� oadaP�t Uaf �
õ� G � at Uaf � � p � � �o �� UaoifR� �f � a� at � �f � �f f � m� �f � �� oacmgaf � fMsamU�f � �� mp : omt Rt c)��
6M� � � UafUa� aPa� fao� oa�d m5� � ap � � � � �� p �a (� � : �m� a� �� � om�t � �� , � : o � �t � Mf � t �p � o� � oaf � : dmp I oe� f )�
�7M� � � � Mp at U�� � � f � oafMdU� f � mt � dMi� : ad � p at f � >� p �o � � oaf � mt b op �R � f � a� � � ��
� o p ff p �) �
Imprinting como forma de regulação epigenética Imprinting como forma de regulação epigenética
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Hereditariedade���������������������
mitocondrial
• � V� � � � � l � � r � � gV� p� r � � � � da m� � o � g� V � �
• f o � r � � � � � g� � f r � � f � gV� ro ag� o � f � e� � I � � f � � � �
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• � rl � � a � a� � � � r � � f � � � � o agf � f � Va� d.�
• o f d� � vd� � � aV� vd� V� � f o � 5EM/EC� � l �
• 6: � e� � r � �
• H� � � � V� � 1� �
• HH� � � � g� � � � � �
• 56� � f � a � � � f � l f dal � l é � � f rõ�
• � á � aef � e� � n � f � l Vál Vaf �
• C6P� � f o � gV� � v � � f � 3� vr� � a� � � � � a gVc � rõ�
A mitocondria A mitocondria
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Heteroplasmia vs
Homoplasmia
Bottle-neck
Mosaicismo somático
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� it )� � amch� k� � t � ab�d p mad : �R � � a� o f �t Ua� � M� �c M ���Sç� � t � a� Pm ���
ü � m: U t m�( � �t oa2m�� a� PI p mU f(� moomU�� mdm � a(� � t PMdfgaf)� �
� : I f � � : omp amo � �t � ��
ü � � me� Md � a� t �� p �o � h�( � �ü � � U�2 m�( � mf �o Uom�( � �ü � � acoaff � � mt Uada� UM�d (� �ü � � mfUCo� m f � �� oaf: mo�� � � �ü � � dUao�� gaf � @�d p dI cm� �f � �
Síndrome de Leigh Síndrome de Leigh
ü � o�D Ma5�� p Mf � Md�o (� b� mc�) �
ü � @�d p : dacm�� a2Uaot �� : o coaffmP�( � �
ü � acat ao� � � � �� oaRt �� a� a: mUndm � : mcp at U�o )� �
ü � �m2�� afU� UMo�( � fmt �mf � a� mfbMt � � � � aoa� ad�o �� p � �U � 2m�( � � d DMam � a� � t M� � � � �o i�� �fmt U p �R � (� m�� aUaf � p addmUMf)))�
Síndrome de Kearns-Sayre Síndrome de Kearns-Sayyre
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ü � m : �R �� p mU � t om�d (� �
ü at � ab�d : �R �( � �
ü �� m fa� d�R � �� a� �
ü a: mfI m f � “fUo uavdmua”�
MELAS MELAS
Doenças���������������������
Digénicas
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• � p � �d cMt f � � �f fN� haoa mU�o ma � a� � d�o �p at Ua� mcnt m� �N �
ü � � : oafat � �� a� >� p MU�� gaf � ap � cat af �t � � dmc� f � � �M f �� �� at � � �
ü � at I R: � t � � �: �o at Ua� t �� : oafat � �� a�f I � � p MU� � � �
� p � � p MU�� � � t Mp � cat a� : a� � �M f �o � at � ��
� � � � � �f � : a� Uao� : at aUo�t � m�� P�o m�P ad)�
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� � � �• � � � � � �• � acat ao� � � � �� � aRt � �• � dm �� Rdm� �• � � afm � a�
� at afN�• � � � S � õSSDSêG�• � � � >� õSàD>SG�• � � � ê� õê: Sêv: S>G�• � � � á� õSZD>>)êG�• � � � Z � õ>DêSG�• � � � à� õ>T: S>G� �
Síndrome de Bardet-Biedl Síndrome de Bardet-Biedl
• � � � �• � o p � � mU : at m��
hm: p ac�d � iR� �� � B� �M f. t � m�� �o� m )� �
• � 2: oaffmPm � a� P�o m�P adN�• � t p �d m�f � � �• � t p �d m�f � afDMadnR� �f �• � �d b op � � gaf � � �o m�� �f �
�• � � ada� � � D>S)S� B� F� �
• � vp : d� F�• � � � F�
Thrombocytopenia-absent radius (TAR) Thrombocytopenia-absent radius (TAAAR)
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Doenças���������������������
genéticas complexas
� � � rvdg� o � � � � a g� V� � � � f � � f o l d� x� � � � � p� Vaf r� � � � gf V� r � � � � l V� � arl f ra� � f .�
ü � � ánl f � � o � p� Vaf r� df � a�
ü � xl f ra� c � r � � o � a� � a� ar�
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" � � : o : o� � � �� P�o m�� mdm � a� bat E: m� � � DMa� a: at a� a� b� � U oaf � cat nR� f �
" � at I R: � õ� G� k� � at R: � õ� G� B� � p � mat Ua� õ� G�
Heritabilidade Heritaaabilidade
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§ � � �§ � : mda: fm� �§ � d�M � p � �§ m: aoUat f � �§ � at � �� mt z �p �U I om� �
mt UafRt �d �§ � at � �� � �o i�� �� mfDMnp m� � �§ � o p � fa�§ � at � �� � m: d�o � �§ � f � dao fa� p CdR: d� �§ � at � �� a� � �o umt f t �§ m: f : � m�f �
§ � at �� � : �d �U , � d� � m �§ � mf: d�f m�� � t cnt mU�� �� �t � ��§ � abamU f � � �o i�� f �
� t cnt mU f �§ � abamU f � � UM� � t aMo�d �§ � fUat fa� : mdI om� ��§ � n� � U �§ � fp ��§ � MRfp �§ � oUomUa� oaMp �U I m a�§ � fDMm5 boat m��
Exemplos de doenças complexas / multifactoriais Exemplos de doenças complexaaas / multifactoriais
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5M � l V� r � g� o � � eV� e� � � f � � � o ada� VM�
HM � f � � � o f rgV� o � l � � V� f � o � � � da� f � rao l d� r � � � �m� V� � ag� Va� � � � � M�
6M � ar� f � V� d� npf � � vo � g� � f � � � � � o sda� � � � � vo � � � � � g� � f � �
� � � r � o � f r � � f o v r� � o � l � V� g� r � o � ar� � � � rg� � f rM� �
� � � af V� � f � f V� � � a� � � o � e� o � f r � � � � � f � ! v � � � � M�
� � ar� f � o � af V� r � � o � ar� l � rrf � r � � � � � g� � � r �
5M � � � gV� � a� � p� Va� p� dM�
HM o l f Vg� � a� � � � � � � � gf V� r � � f � e� � n � f rM�
Características da “hereditariedade complexa” Características da “hereditaaariedade complexaaa”
+ Epigenética
DTN
O Exemplo do DTN OOOOOOOOO EEEEExemplo do DDDDDDTTTNNNNN
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fl� � � � � � � � � � � � � � � � � � � � � � � � � � � � � V� � arl f ra� � f � � � � � � � � � � � � � � � � � � � � � � � � � L �
�V�!
v� �a��
Para cada variante que confere predisposição: Para cada vaaariante que confere predisposição:
Exemplo: Exemplo:
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ü � “� vr� � l n� ada� � � � ” à� � � � � � � � � � � � � � � � � �
ü � p � mt mPm M � n� j at Uaé� fa� �� fM�� dm�� mdm � a� fa� d � �d m5�� �� sMf �t Ua� a� Mp � dmp m�o )�
ü � oaDMat Uap at Ua� oa� Mof � �� omf � f � ap : iom� f � t �� : : Md�� � �
ü � ar� f � � � o ada� V.�� ar� f � � � rf dvgf I � ar� f flV� d� npf � �
( � �� V� ! v � � a� � � o � � � o ada� V� r � � � � l � rrf � � � � � � g� � � I � � V� ! v � � a� � � � l f l vd� � � f � e� V� d�
� �ü � Rdm � a� a� aUaop mt �o � � omf � � oad�R P � ap � �� t fadh�p at U � cat nR� �ü � � 2ap : d � �� � � � �
§ � oaDM. t � m�� ap � mop � f � k� à; � �§ � oaDM. t � m�� t �� : : Md�� � � cao�d k� T)á; � �§ � mf � � oad� RP � : �o � � mop � fk� à; , T)á; � kSZ� �
Cálculo de risco Cálculo de risco
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Cálculo de risco Cálculo de risco
Factores que afectam o RR:
• Relação familiar com o probando
• Gravidade da doença
• O nº de afectados na família
• O sexo do probando
• Consanguínidade
Cálculo de risco Cálculo de risco
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