Monogenic disorders

Monogenic disorders

1. MONOGENIC
DISORDERS
Mariana Roldán Isaza
Medicine Student
ThirdSemester
2-2017

2. MEDICAL UTILITY BIBLIOGRAPHY MONOGENIC DISORDERS
By: Mariana Roldán Isaza
Molecular Biology
Teacher: Lina Martinez
CentrodeMedicinaEmbrionaria.(2013).
Enfermedades monogénicas hereditarias:
CentrodeMedicinaEmbrionaria.Obtenidode
CentrodeMedicinaEmbrionariaSitioWeb:
http://www.pgdcem.com/terminologia/enfer
medades_hereditarias_monogenicas .html
MartínezSánchez,LinaMaría.Biología
Molecular.7ed.Medellín:UPB.Fac.Medicina
UniversityofLeicester.(s.f.).VirtualGenetics
EducationCentre:UniversityofLeicester.
ObtenidodeUniversityofLeicesterWebSite:
http://www2.le.ac.uk/projects/vgec
/healthprof/topics/patterns-of-
inheritance/patterns-of-inheritance-conditions
Thankstothesenew
discoveriesandresearch,
itisgettingcloserand
closertofindingapossible
treatment forthese
genetic diseases,
potentiallylife-threatening
and,untilnow,completely
incurable.
Themedicalutilityithason
musclesinDMDisthat
eveninthelackof
dystrophin,itwillbe
possibletousebrain
stimulusasatreatmentto
improvetheconditions
andqualityoflifeof
patientswithDMD.
Andonthemucousmembranes,thisdiscoverymaybe
oneofthenextwaystosolvethemainproblemof
cysticfibrosis,whichistheobstructionofdifferent
organscoveredbymucus-secretingepithelia,
ThiswillprovidepatientswithCysticFibrosisand
DuchenneMuscularDystrophygreaterlifeexpectancy
andabetterqualityoflife.

3. INTRODUCTION CYSTIC FIBROSIS ALTERS THE
STRUCTURE OF MUCUS IN AIRWAYS
RESTORING BREATHING CAPACITY
IN DUCHENNE MUSCULAR
DYSTROPHY BY ACTIVATING THE
BRAIN
Whenitcomestothegenome,itreferstotheset
ofchromosomesthatcontainallthegenetic
informationthatindividuallyidentifieswhowe
are.Itishighlyprotectedbydifferentcellular
mechanismsforthepurposeofmaintainingthe
DNAstructureandpreventingchangesinits
information.Sometimes,thesemechanismsfailto
correctthedamage,sotheyremaininthecell
andmanagetotransmittotheirdescendants.
Productofthesemutationscanbemonogenic
disorders.Theseinvolvedamageormutationin
thesequenceofasingleDNAgene.Theseare
notnecessarilyhereditary,butcanalsooriginate
spontaneously.Manyofthesearegoingtoimply
agenerallynegativechangefortheonethat
expressesthatmutation,whichcausesdifferent
diseases.
Inaninvestigationconductedat
UniversityCollegeCork,withthe
collaborationoftheUniversityof
CalgaryandTrinityCollegeDublin,
suggestthatbystimulatingbreathing
atthebrainlevel,itispossibleto
decreasetherespiratoryinsufficiency
ofpatientswithDuchenneMuscular
Dystrophy(DMD).
DMDisageneticneuromuscular
diseaselinkedtotheXchromosome
inwhichitdecrements the
production ofdystrophin,an
essentialproteinformuscular
integrity.
Experimentingwithmice with
dystrophindeficiency,whichhad
deteriorationintherespiratory
controlsystem,obtainedthatthe
braincompensated thedeficiency
stimulatingtheactivationofthe
diaphragm(mainmuscleofthe
respiration).
Studentopinion:
Liketheauthorsoftheresearch,I
believethathumanstudiesshould
be done regarding this
compensationtoseeifthismaybea
potentialtreatmentforDMD.
InanewstudypublishedinProceedingsoftheNational
Academy ofSciences,theyobservedhowmucus
structurechangesinpatientswithcysticfibrosis.
Cysticfibrosisisanautosomalrecessivediseaseinwhich
adefectivechloridesecretionisevidencedleadingto
animbalanceoftransportofwaterandelectrolytes
causingtheproductionofadensemucus,difficultto
displacewhichcontributestorecurrentinfections.
Thedifferentresearchersfocusedtheshiftoftwo
proteins,MUC5BandMUC5AC,whichareimportant
components ofmucus.When secretedbythe
submucosalglandsandgobletcells,respectively,they
combinewhatmaybeusefultotrapandremove
particles.Thechangeinproteinstructureisrelatedtoits
accumulationandviscosity.
Studentopinion:
Iconsiderthisagreat
discoverywithwhichwe
canunderstandalittle
moreaboutthisdisorder;as
wellasbeingagreat
opportunitytodiscoverthe
bestwaytotreatthis
deadlydisease.

4. INTRODUCTION
Whenitcomestothegenome,itrefersto
thesetofchromosomesthatcontainall
thegeneticinformationthatindividually
identifieswhoweare.Itishighlyprotected
bydifferentcellularmechanismsforthe
purposeofmaintainingtheDNAstructure
andpreventingchangesinitsinformation.
Sometimes,thesemechanisms failto
correctthedamage,sotheyremaininthe
cellandmanage totransmittotheir
descendants.Productofthesemutations
canbemonogenic disorders.These
involvedamage ormutationinthe
sequenceofasingleDNAgene.Theseare
notnecessarilyhereditary,butcanalso
originatespontaneously.Manyofthese
aregoingtoimplyagenerallynegative
changefortheonethatexpressesthat
mutation,whichcausesdifferentdiseases.
INTRODUCTION
ThissectiondiscussesDNAmutations,theproductof
failureintherepairmechanismsofthecells.
Inthecellcyclethereare3controlpoints(inphase
G1,G2andM)whichcheckthattheDNAisnot
damaged, thattherearenoportionswithout
replicate,andthatthechromosomesarecorrectly
positionedinthemitoticspindleforitslater
distributiontothedaughtercells.
Takingintoaccountthedefinitionof"monogenic
disorders",andthatageneisaDNAsequence
codingforaproteinthathasaspecificfunctionin
thecell,thedamage inthisanditssubsequent
transmissionwouldimplythemalfunctionofthecells
thatcodingforthismutation.
Monogenetic disorderscanbeinheritedwith
differentpatternswhichcanbe:
•AutosomalRecessiveInheritance
•AutosomalDominantInheritance
•X-LinkedRecessiveInheritance
•X-LinkedDominantInheritance

5. CYSTIC FIBROSIS ALTERS THE
STRUCTURE OF MUCUS IN
AIRWAYS
InanewstudypublishedinProceedingsof
theNationalAcademy ofSciences,they
observedhowmucusstructurechangesin
patientswithcysticfibrosis.
Cysticfibrosisisanautosomalrecessive
diseaseinwhichadefectivechloride
secretionisevidencedleadingtoan
imbalanceoftransportofwaterand
electrolytescausingtheproductionofa
densemucus,difficulttodisplacewhich
contributestorecurrentinfections.
Thedifferentresearchersfocusedtheshiftof
twoproteins,MUC5BandMUC5AC,which
areimportantcomponentsofmucus.When
secretedbythesubmucosalglandsand
gobletcells,respectively,theycombinewhat
maybeusefultotrapandremoveparticles.
Thechangeinproteinstructureisrelatedto
itsaccumulationandviscosity.
Studentopinion:
Iconsiderthisagreat
discoverywithwhich
wecanunderstanda
littlemoreaboutthis
disorder;aswellas
being a great
opportunity to
discoverthebestway
totreatthisdeadly
disease.
CYSTIC FIBROSIS ALTERS THE
STRUCTURE OF MUCUS IN AIRWAYS
June 28, 2017
University of Iowa
Health Care

6. CYSTIC FIBROSIS ALTERS THE
STRUCTURE OF MUCUS IN AIRWAYS
Cysticfibrosisiscausedbyamutationina
genelocatedonchromosome 7that
codes forCFTR (CysticFibrosis
Transmembrane Conductance
Regulator)which,asthenameimplies,is
aproteinthatregulatestheconductance
ofchlorinethroughmembranes in
epithelialcells.Sincethesecellsarefound
in various systems (airways,
gastrointestinaltract,liver,pancreas),itis
alife-threateningdiseaseforthosewho
expressit.

7. CYSTIC FIBROSIS ALTERS THE
STRUCTURE OF MUCUS IN AIRWAYS
Theproductionofmucusisessential
fortheinhaledsubstanceentrapment,
includingvirusesandbacteria,which
canbeharmfulandcaninterferewith
thegasexchange.Then,thankstothe
cilia(smallprojectionsonthesurface
oftheairwaycells)theproduced
mucusissweptoutwards.

8. CYSTIC FIBROSIS ALTERS THE
STRUCTURE OF MUCUS IN AIRWAYS
MUC5Bisproducedasstrands,whileMUC5ACis
secretedasfinethreadsandthinsheets.Itwas
shownthatthesetwotypesofproteinare
combinedbyexitingthesurfaceoftheviaareas
sothattheMUC5Bstrandsarepartiallycovered
withMUC5ACsheets.Saidstructuremaybe
usefulforcapturingandremovinginhaled
particles.However,CF-affectedanimalsshowed
thattheMUC5Bstrandsareentangled,which
continuallyfilltheductsofthesubmucosal
glandsandreleasethemeasily,andthe
MUC5ACsheetsarelargerandplentiful.

9. STUDENT OPINION
I believe that this new finding may help to understand a little more about the disease
and the changes that it entails. I also find it surprising how changing a few base pairs in
our DNA can entail such serious damage to our health.

10. RESTORING BREATHING CAPACITY IN
DUCHENNE MUSCULAR DYSTROPHY
BY ACTIVATING THE BRAIN
September26, 2017
ThePhysiologicaSociety
RESTORING BREATHING
CAPACITY IN DUCHENNE
MUSCULAR DYSTROPHY BY
ACTIVATING THE BRAIN
Inaninvestigationconducted
atUniversityCollegeCork,
withthecollaborationofthe
UniversityofCalgaryand
TrinityCollegeDublin,suggest
thatbystimulatingbreathing
atthebrainlevel,itispossible
todecreasetherespiratory
insufficiencyofpatientswith
Duchenne Muscular
Dystrophy(DMD).
DMD is a genetic
neuromusculardiseaselinked
totheXchromosome in
whichitdecrements the
productionofdystrophin,an
essentialproteinformuscular
integrity.
Experimentingwithmicewith
dystrophindeficiency,which
haddeteriorationinthe
respiratorycontrolsystem,
obtainedthatthebrain
compensatedthedeficiency
stimulatingtheactivationof
thediaphragm(mainmuscle
oftherespiration).
Studentopinion:
Liketheauthorsofthe
research,Ibelievethat
human studiesshouldbe
done regarding this
compensationtoseeifthis
maybeapotentialtreatment
forDMD.

11. RESTORING BREATHING CAPACITY IN
DUCHENNE MUSCULAR DYSTROPHY
BY ACTIVATING THE BRAIN
DMDdamagestheDMDgenelocated
attheXp21locus.Affectedchildrenwill
bedelayedinmotordevelopment,
whichimpedesadequatemobility.

12. RESTORING BREATHING CAPACITY IN
DUCHENNE MUSCULAR DYSTROPHY
BY ACTIVATING THE BRAIN
Dystrophinisacytoskeletalproteinfound
ontheinnerfaceofthecellmembrane.
Itsfunctionistomaintaintheintegrityof
musclefibersthroughinteractionswith
othermembrane proteins.Thankstoits
deficiency,musclecellsareeasily
damagedandlimitmusclecontraction.

13. RESTORING BREATHING CAPACITY IN
DUCHENNE MUSCULAR DYSTROPHY
BY ACTIVATING THE BRAIN
Thediaphragmisinnervatedbythe
mainlyphrenicnerves,whichcomefrom
therootsofC3,C4andC5.Thestimulus
sentbythebraintothediaphragmto
enhance itsfunctioningasa
compensatorymechanism,shouldbeby
theseroots.

14. STUDENT OPINION
Itissurprisingtoknowthatthechangeinasingleproteinofthemusclefiberscanalter
themuscleuntilitleadstodysfunction.Ibelievethatthisdiscoverycanprovideagood
basisforthinkingaboutapossibletreatmentofthisdisease.

15. MEDICAL UTILITY
MEDICAL UTILITY
Thankstothese
newdiscoveries
andresearch,it
isgettingcloser
andcloserto
finding a
possible
treatment for
these genetic
diseases,
potentiallylife-
threateningand,
until now,
completely
incurable.
Themedicalutilityithasonmusclesin
DMDisthateveninthelackof
dystrophin,itwillbepossibletouse
brainstimulusasatreatmentto
improvetheconditionsandqualityof
lifeofpatientswithDMD.
Andonthemucousmembranes,this
discoverymaybeoneofthenext
waystosolvethemainproblemof
cysticfibrosis,whichistheobstruction
ofdifferentorganscoveredbymucus-
secretingepithelia,
ThiswillprovidepatientswithCystic
FibrosisandDuchenne Muscular
Dystrophygreaterlifeexpectancyand
abetterqualityoflife.

16. MEDICAL UTILITY
Increasingthefrequencyofbrainstimulifor
potentialmuscleactivationinDMDand
knowingthestructureoftheproteinsthat
comprisemucusinCFmayperhapsbea
possibletreatmentforthesetwogenetic
diseases.

17. MEDICAL UTILITY
Allthesestudiescancontributetoimprove
thequalityoflifeofpatientswhohave
diseasesthathavenospecifictreatment
sofar.

18. MEDICAL UTILITY
Theaboveinformationcanguideustoa
betterunderstandingofmonogenic
disorders,toincreaseourknowledge
aboutheredity,andtointernalizethe
importanceofthehumangenomeand
geneticsinthestudyofpathologies.

19. BIBLIOGRAPHY
AsociaciónDuchenneParentProjectEspaña.(25deSeptiembrede2012).
¿QuéesDuchenne?:AsociaciónDuchenneParentProjectEspaña.Obtenido
de Asociación Duchenne ParentProjectEspaña Web Site:
https://www.duchenne-spain.org/que-es-duchenne/
CentrodeMedicinaEmbrionaria.(2013).Enfermedades monogénicas
hereditarias:CentrodeMedicinaEmbrionaria.MedicinaEmbrionariaWebSite:
http://www.pgdcem.com/terminologia/enfermedades_hereditarias_monogen
icas.html
Escobar,H.,&Sojo,A.(2010).FibrosisQuística.EnA.E.Pediatría,Protocolos
Diagnóstico-TerapéuticosdeGastroenterología,HepatologíayNutrición
Pediatrica.ErgónS.A.ObtenidodeAsociaciónEspañoladePediatríaWeb
Site:http://www.aeped.es/sites/default/files/documentos/10-FQ.pdf
MartínezSánchez,LinaMaría.BiologíaMolecular.7ed.Medellín:UPB.Fac.
Medicina
UniversityofLeicester.(s.f.).VirtualGeneticsEducationCentre:Universityof
Leicester.UniversityofLeicesterWebSite:http://www2.le.ac.uk/projects/vgec
/healthprof/topics/patterns-of-inheritance/patterns-of-inheritance-conditions