mutasi

MUTASI MUTASI MUTASI MUTASI

Kiagus Muhammad ArsyadKiagus Muhammad ArsyadBagian Biologi Kedokteran dan AndrologiBagian Biologi Kedokteran dan Andrologi

Fakultas Kedokteran UNSRIFakultas Kedokteran UNSRI

11KMA MUTASI KHROMOSOM GENEKMA MUTASI KHROMOSOM GENE

TUJUAN PEMBELAJARANTUJUAN PEMBELAJARAN

Agar mahasiswa mampu mengetahui dan Agar mahasiswa mampu mengetahui dan memahami tentang :memahami tentang :

1.1.MutasiMutasi

2.2.Penyebab MutasiPenyebab Mutasi

3.3.Penyakit akibat mutasiPenyakit akibat mutasi

4.4.Terapi genetik untuk berbagai penyakit Terapi genetik untuk berbagai penyakit genetik.genetik.


MATERI PEMBELAJARANMATERI PEMBELAJARAN

1.1. PendahuluanPendahuluan

2.2. Penyebab MutasiPenyebab Mutasi

3.3. Macam MutasiMacam Mutasi

4.4. Penyakit akibat mutasiPenyakit akibat mutasi

5.5. Terapi genetikTerapi genetik


Menurut Biologi, MUTASIMenurut Biologi, MUTASI adalah setiap adalah setiap perubahan fisik pada materi genetik dari suatu perubahan fisik pada materi genetik dari suatu organisme.organisme.

Hampir sebagian besar kasus terjadi pada Hampir sebagian besar kasus terjadi pada DNA atau RNA didalam inti sel. DNA atau RNA didalam inti sel.

Pada organisme multicellular ada 2 macam Pada organisme multicellular ada 2 macam kelas yaitu :kelas yaitu :

1.1. Germ line mutationGerm line mutation, dan , dan

2.2. Somatic MutationSomatic Mutation. .


Faktor penyebab:Faktor penyebab:1.1. Internal, Internal,

penyebab adalah errors pada penyebab adalah errors pada reproduksi materi genetik. reproduksi materi genetik.

2.2. External, External, yang sering radiasi yang sering radiasi ultraviolet, , chemical chemical mutagens, atau , atau parasitic organisms ( parasitic organisms (virus atau atau bacteria). ).


ENVIRONMENT :1. INTERNAL2. EXTERNAL

GENE MUTATION

POLYMORPHISM

ABNORMALPHENOTYPE


Disease risk

Prevention of inherited traits:Decision not to reproduceFetal destructionAbortion

Environmental exposure

Genetic mutations and

polymorphisms

Reduction in mutagens

Mutagens

Genetic risks

Gene therapy

To prevent second hit

Environmental risk

Radiation and environmental exposure:BiologicalPhysicalSocioeconomic

Behavioral changes:SmokingDietExerciseDrugs & alcohol

Other measures:ChemopreventionEarly detectionPopulation screeningRemoval of target organs

Disease

Inheritance


Ada 2 macam Mutasi :Ada 2 macam Mutasi :

1.1.Mutasi pada Gene (Point Mutation)Mutasi pada Gene (Point Mutation)

2.2.Mutasi pada khromosom Mutasi pada khromosom


DEFINISI DEFINISI ::

Perubahan Susunan Nukleotida DNAPerubahan Susunan Nukleotida DNA

JENIS :JENIS : Mutasi TitikMutasi Titik

DelesiDelesi

InsersiInsersi

AKIBAT AKIBAT ::

t.a.at.a.a

Fungsi Fungsi

FungsiFungsi

Tak berfungsi (inactivated)Tak berfungsi (inactivated)

LOKASI LOKASI ::

Sel benih Sel benih Peny. Keturunan Peny. Keturunan

Sel Somatik Sel Somatik Kanker Kanker

DNA Mitokondria DNA Mitokondria

(menimbulkan penyakit yang diwariskan (menimbulkan penyakit yang diwariskan garis keturunan ibu)garis keturunan ibu)


1 Klas mutasi 1.1 Deletion mutations 1.2 Insertion mutations 1.3 Substitution mutations

2 Subklas Mutasi 2.1 Morphological 2.2 Biochemical 2.3 Lethal 2.4 Loss-of-function 2.5 Gain-of-function 2.6 Dynamic mutation 2.7 Frame shift mutation


Crossing overCrossing over


Non DysjunctionNon Dysjunction


Extra sex chromosomeExtra sex chromosome


KELAINAN SEKS KHROMOSOMKELAINAN SEKS KHROMOSOM

Kelainan seks khromosomKelainan seks khromosom1.1. Khromosom Y : lengan p & q, Y linked Khromosom Y : lengan p & q, Y linked

gen, TDF, SRY, AZFa,AZFb,AZFc,DAZgen, TDF, SRY, AZFa,AZFb,AZFc,DAZ2.2. Khromosom X : XIST, XiKhromosom X : XIST, Xi3.3. Macam kelainan seks khromosom : Pria Macam kelainan seks khromosom : Pria

= 47,XXY,48XXXY, 47XYY, XX = 47,XXY,48XXXY, 47XYY, XX males,males,

4.4. Wanita= XO,Trisomy X, XY females, Wanita= XO,Trisomy X, XY females, Androgen insensitivityAndrogen insensitivity


KHROMOSOMAL ABNORMALITY KHROMOSOMAL ABNORMALITY SYNDROMESYNDROME

1.1. Down Syndrome.Down Syndrome.

2.2. Trisomy 18 Syndrome,Trisomy 18 Syndrome,

3.3. Trisomy 13 syndrome,Trisomy 13 syndrome,

4.4. Trisomy 8 Syndrome,Trisomy 8 Syndrome,

5.5. Trisomy 9 Mosaic syndrome,Trisomy 9 Mosaic syndrome,

6.6. Triploidy Syndrome and Diploid/Triploid Mixoploidy Triploidy Syndrome and Diploid/Triploid Mixoploidy Syndrome,Syndrome,

7.7. Deletion 2p syndromeDeletion 2p syndrome

8.8. Duplication 3q syndrome,Duplication 3q syndrome,

9.9. Deletion 4p syndrome,Deletion 4p syndrome,

10.10. Duplication 4syndrome,Duplication 4syndrome,2323KMA MUTASI KHROMOSOM GENEKMA MUTASI KHROMOSOM GENE


11. Deletion 4q syndrome,11. Deletion 4q syndrome,12. Deletion 5 p syndrome,12. Deletion 5 p syndrome,13. Deletion 9p syndrome,13. Deletion 9p syndrome,14. Duplication 9 p syndrome,14. Duplication 9 p syndrome,15. Duplication 10q syndrome,15. Duplication 10q syndrome,16. Aniridia-Wilms Tumor Association,16. Aniridia-Wilms Tumor Association,17. Deletion 11q syndrome,17. Deletion 11q syndrome,18. Deletion 13q syndrome,18. Deletion 13q syndrome,19. Duplication15q syndrome,19. Duplication15q syndrome,20. Deletion 18p syndrome,20. Deletion 18p syndrome,21. Deletion 18q syndrome,21. Deletion 18q syndrome,



22. Cat-eye syndrome22. Cat-eye syndrome23. XYY Syndrome,23. XYY Syndrome,24. XXY Syndrome, Klinefeleter syndrome,24. XXY Syndrome, Klinefeleter syndrome,25. XXXY and XXXXY Syndrome,25. XXXY and XXXXY Syndrome,26. XXX and XXXX syndrome26. XXX and XXXX syndrome27. XXXXX syndrome27. XXXXX syndrome28. XO syndrome28. XO syndrome


Table 11.1Table 11.1


4. MUTASI DINAMIK4. MUTASI DINAMIK

Penyakit yang timbul akibat mutasi yang Penyakit yang timbul akibat mutasi yang khas yaitu Mutasi dinamik khas yaitu Mutasi dinamik dimana suatu dimana suatu elemen heritable yang tidak stabil dimana elemen heritable yang tidak stabil dimana probalitas dari mutasi tergantung dengan probalitas dari mutasi tergantung dengan jumlah kopi yang bermutasi.jumlah kopi yang bermutasi.Karena itu produk replikasi dari mutasi dinamik Karena itu produk replikasi dari mutasi dinamik akanberbeda dari pewarisnya (predecessor). akanberbeda dari pewarisnya (predecessor). Mutasi ini dicirikan dengan pengulangan Mutasi ini dicirikan dengan pengulangan sekuens pendek berkali kali, menimbulkan sekuens pendek berkali kali, menimbulkan berbagai penyakit termasuk berbagai penyakit termasuk Trinucleotide repeat Trinucleotide repeat disorders.disorders.



Robert I. Richards and Grant R. Sutherland Robert I. Richards and Grant R. Sutherland menyebut phenomena ini, dalam kerangka menyebut phenomena ini, dalam kerangka dynamical genetics, sebagai dinamika mutasi , sebagai dinamika mutasi Ekspansi Triplet disebabkan oleh slippage Ekspansi Triplet disebabkan oleh slippage semasa replikasi DNA. semasa replikasi DNA. Karena pengulangan sekuens DNA pada Karena pengulangan sekuens DNA pada daerah struktur 'loop out' mungkin terbentuk daerah struktur 'loop out' mungkin terbentuk semasa replikasi DNA memungkinkan semasa replikasi DNA memungkinkan disintesanya penambahan pasangan basa disintesanya penambahan pasangan basa complementary base diantara pita ortu dan complementary base diantara pita ortu dan anaknyaanaknya



Contoh Mutasi dinamik :Contoh Mutasi dinamik :1. Fragile X syndromes 2. Huntington's Chorea 3. Myotonic dystrophy 4. Spinobulbar muscular atrophy 5. Spinocerebellar ataxia type 3 6. Friedreich ataxia 7. Ocularpharyngeal muscular dystrophy 8. Progressive myoclonus epilepsy 9. Creutzfeldt-Jakob disease


1. 1. FRAGILE X SYNDROMEFRAGILE X SYNDROME

Fragile X syndromeFragile X syndrome, atau , atau Martin-Bell Martin-Bell syndromesyndrome, adalah suatu sindroma , adalah suatu sindroma genetik dengan manifestasi beragam pada ciri2 fisik, dengan manifestasi beragam pada ciri2 fisik, intelektual, emosional dan gambaran perilaku intelektual, emosional dan gambaran perilaku dari ringan sampai berat.dari ringan sampai berat.Fragile X syndrome adalah bentuk retardasi Fragile X syndrome adalah bentuk retardasi mental yang disebabkan oleh mutasi gen pada mental yang disebabkan oleh mutasi gen pada khromosom X. disebut demikian karena lengan khromosom X. disebut demikian karena lengan panjang khromosom X tampak seperti panjang khromosom X tampak seperti pecah/retakpecah/retak


Penyebab Fragile X syndromePenyebab Fragile X syndromeThe fragile X syndrome is a The fragile X syndrome is a genetic disorder caused by caused by mutation of the of the FMR1 gene on the on the X chromosome. . Mutation at that site is found in 1 out of about every 2000 Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 259 and 1 out of about every 259 females. (Incidence . (Incidence of the disease itself is about 1 in every 4000 females.)of the disease itself is about 1 in every 4000 females.)Normally, the Normally, the FMR1 gene contains between 6-55 (29 in gene contains between 6-55 (29 in Robbins-Kumar pathology textbooks)repeats of the CGG Robbins-Kumar pathology textbooks)repeats of the CGG codon ( (trinucleotide repeats). In people with the fragile X ). In people with the fragile X syndrome, the FMR1 syndrome, the FMR1 allele has over 230-4000 repeats has over 230-4000 repeats of this codon.of this codon.[4]Expansion of the CGG repeating codon to such a degree Expansion of the CGG repeating codon to such a degree results in a results in a methylation of that portion of the of that portion of the DNA, , effectively silencing the expression of the FMR1 effectively silencing the expression of the FMR1 protein..


Transmisi fragile X Transmisi fragile X

Males with the fragile X cannot transmit it to any of their Males with the fragile X cannot transmit it to any of their sons (since males contribute a Y chromosome, not an X, sons (since males contribute a Y chromosome, not an X, to their male offspring), but will transmit it to all of their to their male offspring), but will transmit it to all of their daughters, as males contribute their X to all of their daughters, as males contribute their X to all of their daughters.daughters.Females carrying one copy of the fragile X can transmit it Females carrying one copy of the fragile X can transmit it to their sons or daughters; in this case each child has a to their sons or daughters; in this case each child has a 50% chance of inheriting the fragile X. Sons who receive 50% chance of inheriting the fragile X. Sons who receive the fragile X are at high risk of intellectual disability. the fragile X are at high risk of intellectual disability. Daughters who receive the fragile X may appear normal Daughters who receive the fragile X may appear normal or they may be intellectually disabled, usually to a lesser or they may be intellectually disabled, usually to a lesser degree than boys with the syndrome. The transmission degree than boys with the syndrome. The transmission of fragile X often increases with each passing of fragile X often increases with each passing generation. This seemingly anomalous pattern of generation. This seemingly anomalous pattern of inheritance is referred to as the inheritance is referred to as the Sherman paradox..


Physical Phenotype Physical Phenotype 1.1. Prominent ears Prominent ears 2.2. Long face (vertical maxillary Long face (vertical maxillary

excess) excess) 3.3. High-arched palate (related High-arched palate (related

to the above) to the above) 4.4. Hyperextensible finger joints Hyperextensible finger joints 5.5. Double-jointed thumbs Double-jointed thumbs 6.6. Flat feet Flat feet 7.7. Soft skin Soft skin 8.8. Larger testicles in men Larger testicles in men

(macroorchidism) (macroorchidism) 9.9. Low muscle tone Low muscle tone


Diagnosis Diagnosis

Fragile X syndrome was originally diagnosed by culturing Fragile X syndrome was originally diagnosed by culturing cells in a folate deficient medium and then assessing the cells in a folate deficient medium and then assessing the cultures for X-chromosome breakage by cultures for X-chromosome breakage by cytogenetic analysis of the long arm of the X chromosome. This analysis of the long arm of the X chromosome. This technique proved unreliable for both diagnosis and technique proved unreliable for both diagnosis and carrier testing.carrier testing.The fragile X abnormality is now directly determined by The fragile X abnormality is now directly determined by analysis of the number of CGG repeats and their analysis of the number of CGG repeats and their methylation status using methylation status using restriction endonuclease digestion and digestion and Southern blot analysis. analysis.


2. HUNTINGTON’S DISEASES2. HUNTINGTON’S DISEASES

Huntington's diseaseHuntington's disease or or choreachorea ( (HDHD) is an ) is an incurable incurable neurodegenerative genetic disorder that typically manifests itself first in middle age. that typically manifests itself first in middle age.

It is the most common genetic cause of It is the most common genetic cause of abnormal involuntary writhing movements called abnormal involuntary writhing movements called chorea. .

It is much less common in people of Asian or It is much less common in people of Asian or African descent than in people from Western African descent than in people from Western Europe Europe


PENYEBAB H.D.PENYEBAB H.D.

The disease is caused by a mutation on either of The disease is caused by a mutation on either of the two copies of a specific the two copies of a specific gene, located on an , located on an autosomal chromosome. .

As the mutation is As the mutation is dominant, each child of an , each child of an affected parent has a 50% chance of inheriting affected parent has a 50% chance of inheriting the disease. In rare situations where both the disease. In rare situations where both parents have an affected gene, or either parent parents have an affected gene, or either parent has two affected copies, this chance is greatly has two affected copies, this chance is greatly increased. increased.


Tanda dan simptom Tanda dan simptom

Symptoms of Huntington's disease commonly become Symptoms of Huntington's disease commonly become noticeable between the ages of 35 and 44 years, but noticeable between the ages of 35 and 44 years, but they can begin at any age from infancy,they can begin at any age from infancy, often when affected individuals have had children.often when affected individuals have had children.In the early stages, there are subtle changes in In the early stages, there are subtle changes in personality, personality, cognition, or physical skills., or physical skills.The physical symptoms are usually the first to be The physical symptoms are usually the first to be noticed, as cognitive and noticed, as cognitive and psychiatric symptoms are symptoms are generally not severe enough to be recognized on their generally not severe enough to be recognized on their own at the earlier stages.own at the earlier stages.Almost everyone with Huntington's disease eventually Almost everyone with Huntington's disease eventually exhibits similar physical symptoms, but the onset, exhibits similar physical symptoms, but the onset, progression and extent of cognitive and psychiatric progression and extent of cognitive and psychiatric symptoms vary significantly between individualssymptoms vary significantly between individuals


Tanda dan simptom Tanda dan simptom

Reported prevalences of behavioral and Reported prevalences of behavioral and psychiatric symptoms in Huntington's psychiatric symptoms in Huntington's diseasedisease[10] Irritability38–73%Irritability38–73%Apathy34–76%Apathy34–76%Anxiety34–61%Anxiety34–61%Depressed mood33–69%Depressed mood33–69%Obsessive and compulsive10–Obsessive and compulsive10–52%Psychotic3–11%52%Psychotic3–11%


PEWARISANPEWARISAN

Huntington's disease has Huntington's disease has autosomal dominant inheritance, meaning that an affected individual inheritance, meaning that an affected individual typically inherits a copy of the gene with an typically inherits a copy of the gene with an expanded trinucleotide repeat (the mutant expanded trinucleotide repeat (the mutant allele) ) from an affected parent.from an affected parent.In this type of inheritance pattern, each offspring In this type of inheritance pattern, each offspring of an affected individual has a 50% chance of of an affected individual has a 50% chance of inheriting the mutant allele and therefore being inheriting the mutant allele and therefore being affected with the disorder (see figure). This affected with the disorder (see figure). This probability is sex-independent.probability is sex-independent.


Diagnosis Diagnosis

Diagnosis of the onset of HD can be made following the Diagnosis of the onset of HD can be made following the appearance of physical symptoms specific to the appearance of physical symptoms specific to the disease.disease. Genetic testing can be used to confirm a physical Genetic testing can be used to confirm a physical diagnosis if there is no family history of HD. Even before diagnosis if there is no family history of HD. Even before the onset of symptoms, genetic testing can confirm if an the onset of symptoms, genetic testing can confirm if an individual or individual or embryo carries an expanded copy of the carries an expanded copy of the HTTHTT gene that causes the disease. gene that causes the disease. Genetic counseling is available to provide advice and is available to provide advice and guidance throughout the testing procedure, and on the guidance throughout the testing procedure, and on the implications of a confirmed diagnosis. These implications implications of a confirmed diagnosis. These implications include the impact on an individual's psychology, career, include the impact on an individual's psychology, career, family planning decisions, relatives and relationships. family planning decisions, relatives and relationships. Despite the availability of pre-symptomatic testing, only Despite the availability of pre-symptomatic testing, only 5% of those at risk of inheriting HD choose to do so.5% of those at risk of inheriting HD choose to do so.


Differential diagnosisDifferential diagnosis

Although HD accounts for ninety percent of the cases of Although HD accounts for ninety percent of the cases of chorea caused by genetic disorders, and an chorea caused by genetic disorders, and an observational diagnosis for someone with typical observational diagnosis for someone with typical symptoms and a symptoms and a family history of the disease is usually of the disease is usually correct, a genetic test is required to rule out other correct, a genetic test is required to rule out other disorders.disorders.[5][39] Most of these other disorders are Most of these other disorders are collectively labelled HD-like (HDL).collectively labelled HD-like (HDL).[39] The causes of The causes of most of these HDL diseases are unknown, but those with most of these HDL diseases are unknown, but those with known causes are due to mutations in the known causes are due to mutations in the prion protein gene (HDL1), the (HDL1), the junctophilin 3 gene (HDL2), a recessively inherited (HDL2), a recessively inherited HTTHTT gene (HDL3 — only gene (HDL3 — only found in one family and poorly understood), and the found in one family and poorly understood), and the gene encoding the gene encoding the TATA box-binding protein (HDL4/ (HDL4/SCA17).).[39][[edit] ]


3. MYOTONIC DYSTROPHY3. MYOTONIC DYSTROPHY

Myotonic dystrophyMyotonic dystrophy ( (dystrophia myotonicadystrophia myotonica, DM) is a , DM) is a chronic, slowly progressing, highly variable inherited , slowly progressing, highly variable inherited multisystemic multisystemic disease that can manifest at any age from that can manifest at any age from birth to old age. birth to old age. It is characterized by wasting of the muscles (muscular It is characterized by wasting of the muscles (muscular dystrophy), posterior subcapsular iridescent dystrophy), posterior subcapsular iridescent cataracts (opacity of the lens of the eyes), heart conduction (opacity of the lens of the eyes), heart conduction defects, defects, endocrine changes and changes and myotonia (difficulty (difficulty relaxing a muscle). Most notably, the highly variable age relaxing a muscle). Most notably, the highly variable age of onset decreases with successive generations. of onset decreases with successive generations. Thus the disease shows at an earlier age in successive Thus the disease shows at an earlier age in successive generations, a phenomenon termed generations, a phenomenon termed anticipation. There . There are two classifications of DM, each having different are two classifications of DM, each having different associated symptoms.associated symptoms.


Klasifikasi Klasifikasi Myotonic dystrophy is the most common form of Myotonic dystrophy is the most common form of muscular dystrophy allowing adult survival and the second most common form of any skeletal allowing adult survival and the second most common form of any skeletal muscle disease after muscle disease after Duchenne muscular dystrophy. There are currently . There are currently two known types of adult onset DM, both identifiable by DNA analysis:two known types of adult onset DM, both identifiable by DNA analysis:Myotonic dystrophy type 1 (DM1), also known as Steinert's disease. DM1 Myotonic dystrophy type 1 (DM1), also known as Steinert's disease. DM1 has a has a congenital form that can severely affect babies and a childhood onset form that can severely affect babies and a childhood onset form. form. Myotonic dystrophy type 2 (DM2), commonly referred to as PROMM or Myotonic dystrophy type 2 (DM2), commonly referred to as PROMM or proximal myotonic myopathy. proximal myotonic myopathy. Type 1 is by far the most common form, accounting for 98% of all myotonic Type 1 is by far the most common form, accounting for 98% of all myotonic dystrophy cases, however DM2 can be more difficult to diagnose because dystrophy cases, however DM2 can be more difficult to diagnose because of unusual phenotypes and is believed to be underdiagnosed.of unusual phenotypes and is believed to be underdiagnosed.Other forms of myotonic dystrophy (DM3, DM4, DMX) are currently Other forms of myotonic dystrophy (DM3, DM4, DMX) are currently suspected by researchers to exist.[suspected by researchers to exist.[citation needed] One recent case was ] One recent case was proposed as a candidate for the "DM3" label,proposed as a candidate for the "DM3" label,[1] but was later characterized but was later characterized as a form of as a form of Paget's disease..[2][3]


Perbedaan DM1 dan DM2 Perbedaan DM1 dan DM2

While both diseases are considered slow While both diseases are considered slow degenerative conditions, conditions, DM2 is considered to be generally milder than DM1. DM2 is considered to be generally milder than DM1. The severe The severe congenital form that affects babies in DM1 has not been form that affects babies in DM1 has not been found in DM2 and the early onset of symptoms is rarely noted to found in DM2 and the early onset of symptoms is rarely noted to appear in younger patients in the medical literature. appear in younger patients in the medical literature. The repeat expansion for DM2 is considerably larger than for DM1, The repeat expansion for DM2 is considerably larger than for DM1, ranging from 75 to over 11,000. ranging from 75 to over 11,000. Unlike DM1, the size of the repeated DNA expansion does not Unlike DM1, the size of the repeated DNA expansion does not appear to make a difference in the age of onset or disease severity appear to make a difference in the age of onset or disease severity in DM2. in DM2. Anticipation is a common feature of DM1. It appears to be less is a common feature of DM1. It appears to be less significant in type 2 and most current reviews only report mild significant in type 2 and most current reviews only report mild anticipation as a feature of DM2. anticipation as a feature of DM2.


SimptomSimptom

Presentation of symptoms varies considerably by form Presentation of symptoms varies considerably by form (DM1/DM2), severity and even unusual DM2 (DM1/DM2), severity and even unusual DM2 phenotypes. DM1 patients often present with phenotypes. DM1 patients often present with myotonia, , disabling distal weakness and severe cognitive disabling distal weakness and severe cognitive problems. DM2 patients commonly present with muscle problems. DM2 patients commonly present with muscle pain, stiffness, fatigue, or the development of proximal pain, stiffness, fatigue, or the development of proximal lower extremity weakness (Day & al, 2003).lower extremity weakness (Day & al, 2003).The characteristic pattern of weakness is different for The characteristic pattern of weakness is different for DM1 and DM2: In DM1, it is noted in face and jaw DM1 and DM2: In DM1, it is noted in face and jaw muscles, the drooping of the eyelids (ptosis), weakness muscles, the drooping of the eyelids (ptosis), weakness of the neck muscles, hands and lower legs. In DM2, the of the neck muscles, hands and lower legs. In DM2, the weakness is more evident in proximal muscles, those weakness is more evident in proximal muscles, those closer to the trunk of the body: neck, shoulders, hip closer to the trunk of the body: neck, shoulders, hip flexors and upper legs.flexors and upper legs.


Genetik Genetik

DM is a genetic condition DM is a genetic condition which is inherited in an which is inherited in an autosomal dominant pattern, autosomal dominant pattern, meaning that inheriting a meaning that inheriting a mutant gene from one parent mutant gene from one parent will result in the condition. will result in the condition. There is a 50% chance of There is a 50% chance of inheriting DM from an affected inheriting DM from an affected parent.parent.DM is one of several known DM is one of several known trinucleotide repeat disorders. trinucleotide repeat disorders. Certain areas of DNA have Certain areas of DNA have repeated sequences of two or repeated sequences of two or three nucleotides.three nucleotides.


DiagnosisDiagnosis

The diagnosis of DM1 and DM2 can be difficult The diagnosis of DM1 and DM2 can be difficult and may be delayed due to the large number of and may be delayed due to the large number of neuromuscular disorders, most of which are very neuromuscular disorders, most of which are very rare.rare.

Neuromuscular disorders can cover more than Neuromuscular disorders can cover more than 40 different diseases and additional forms of 40 different diseases and additional forms of these bring the number of distinct disorders these bring the number of distinct disorders close to 100.close to 100.


Tatalaksana Tatalaksana

There is currently no cure for or treatment specific to There is currently no cure for or treatment specific to myotonic dystrophy. Heart problems, cataracts, and myotonic dystrophy. Heart problems, cataracts, and other abnormalities associated with the condition can be other abnormalities associated with the condition can be treated but not cured. However there are medical treated but not cured. However there are medical interventions and medications that may relieve some of interventions and medications that may relieve some of the symptoms such as myotonia, pain and excessive the symptoms such as myotonia, pain and excessive sleepiness. Some treatments have been subject to sleepiness. Some treatments have been subject to systematic review for safety and efficacy through the systematic review for safety and efficacy through the Cochrane Reviews for symptoms such as hypersomnia Cochrane Reviews for symptoms such as hypersomnia (excessive daytime sleepiness), myotonia, strength (excessive daytime sleepiness), myotonia, strength training and aerobic exercise training and foot drop.training and aerobic exercise training and foot drop.


Skrining Skrining

Screening for the DMPK gene for DM1 is Screening for the DMPK gene for DM1 is targeted at chromosome 19 while the ZNF9 targeted at chromosome 19 while the ZNF9 gene for DM2 is found on chromosome 3. gene for DM2 is found on chromosome 3. Genetic tests, including prenatal testing, are Genetic tests, including prenatal testing, are available for both confirmed forms. Molecular available for both confirmed forms. Molecular testing is considered the gold standard of testing is considered the gold standard of diagnosis. Further forms of myotonic dystrophy diagnosis. Further forms of myotonic dystrophy (DM3, DM4, DMX) are suspected by (DM3, DM4, DMX) are suspected by researchers with possible defects on researchers with possible defects on chromosome 16 and chromosome 21.chromosome 16 and chromosome 21.


4.TERAPI GEN4.TERAPI GEN

1.1. PendahuluanPendahuluan

2.2. Status Terapi gene saat iniStatus Terapi gene saat ini

3.3. Pertimbangan khusus untuk Terapi Pertimbangan khusus untuk Terapi genegene

4.4. Rencana TerapiRencana Terapi

5.5. Masa Depan Terapi GeneMasa Depan Terapi Gene


4.1. Pendahuluan4.1. Pendahuluan

Terapi Genetik adalah penghantaran Terapi Genetik adalah penghantaran materi genetik kedalam sel untuk materi genetik kedalam sel untuk mengembalikan fungsi sel.mengembalikan fungsi sel.Materi genetik yang diberikan dapat Materi genetik yang diberikan dapat berupa : berupa :

1.1. deoxyribonucleic acid (DNA) ataudeoxyribonucleic acid (DNA) atau2.2. RNA, atauRNA, atau3.3. Protein yang berperan pada sejumlah Protein yang berperan pada sejumlah

kasus. kasus.



Perubahan fungsi sel bisa menambah Perubahan fungsi sel bisa menambah atau mengurangi jumlah protein asal atau mengurangi jumlah protein asal yang dihasilkan, atau produksi protein yang dihasilkan, atau produksi protein asing. asing. Pemberian materi genetik bisa Pemberian materi genetik bisa dilakukan dengan dilakukan dengan microinjectionmicroinjection, atau , atau carriercarrier yang berinteraksi dengan yang berinteraksi dengan membrane sel atau terikat protein membrane sel atau terikat protein membrane sebagai bagian pintu masuk membrane sebagai bagian pintu masuk ke dalam sel. ke dalam sel.



PolynucleotidaPolynucleotida bisa berbentuk pita tunggal atau bisa berbentuk pita tunggal atau ganda, dan bisa diberikan code untuk pesan, ganda, dan bisa diberikan code untuk pesan, atau tidak (sebagaimana pada kasus atau tidak (sebagaimana pada kasus pemberian antisense gene). pemberian antisense gene). Walaupun lokasi sel pada waktu pemberian Walaupun lokasi sel pada waktu pemberian gene tidak dibatasi. Sel sisa bagian dari gene tidak dibatasi. Sel sisa bagian dari makhluk hidup, bisa berupa kultur pada makhluk hidup, bisa berupa kultur pada piringan, atau bisa diambil dari organisme, piringan, atau bisa diambil dari organisme, ditransfeksikanditransfeksikan, dan dipindahkan ke dalam , dan dipindahkan ke dalam organisme yang sama atau berbeda pada saat organisme yang sama atau berbeda pada saat diperlukan.diperlukan.



Terapi Gene berkembang setelah Terapi Gene berkembang setelah perkembangan perkembangan teknologi recombinantteknologi recombinant DNA dan berkembang menggunakan DNA dan berkembang menggunakan teknik pemindahan gene teknik pemindahan gene dengan memakaidengan memakai carier viral carier viral dandan nonviral. nonviral.

Teknik teknik ini telah berhasil baik pada Teknik teknik ini telah berhasil baik pada pengobatan penyakit dan berkembang pengobatan penyakit dan berkembang sampai tahap uji klinik yang juga sukses.sampai tahap uji klinik yang juga sukses.


4.2. STATUS TERAPI GENE 4.2. STATUS TERAPI GENE SAAT INISAAT INI

Tujuan terapi gene adalah untuk Tujuan terapi gene adalah untuk menambah, memperbaiki , atau menambah, memperbaiki , atau memblok expresi genesmemblok expresi genes pada pada pengobatan penyakit yang pengobatan penyakit yang inherited, inherited, juga juga non-inherited.non-inherited.

Macam terapi :Macam terapi :

1.1. Somatic versus Germ line gene therapySomatic versus Germ line gene therapy

2.2. Ex Vivo versus in Vivo gene therapyEx Vivo versus in Vivo gene therapy


4.3. PERTIMBANGAN KHUSUS 4.3. PERTIMBANGAN KHUSUS UNTUK TERAPI GENEUNTUK TERAPI GENE

1.1. Penambahan Gene,Penambahan Gene,

2.2. Terapi bloking dan reparasi Gene Terapi bloking dan reparasi Gene (antisense, ribozyme, targeted (antisense, ribozyme, targeted homologous recombination),homologous recombination),

Metoda:Metoda:

1.1. Non viralNon viral (liposomes, Naked DNA), (liposomes, Naked DNA),

2.2. Viral Viral (retrovirus, Adenovirus, Adeno-(retrovirus, Adenovirus, Adeno-associated virus, others vectors)associated virus, others vectors)


4.4. RENCANA TERAPI4.4. RENCANA TERAPI : :

Penyakit genetik dapat diobati pada berbagai Penyakit genetik dapat diobati pada berbagai level sesuai tahap mutasi dari gene.level sesuai tahap mutasi dari gene.

Pengobatan “ pada level of clinical phenotype” Pengobatan “ pada level of clinical phenotype” mengikutkan semua intervensi medik dan mengikutkan semua intervensi medik dan bedah,bedah,

Yang penting pasien diberi edukasi tentang : Yang penting pasien diberi edukasi tentang : a. penyakit genetik, b. keberhasilan, c. a. penyakit genetik, b. keberhasilan, c. komplikasi, d. dampak genetik terapi, dan e. komplikasi, d. dampak genetik terapi, dan e. ketidaknyamanan pengobatan.ketidaknyamanan pengobatan.


LEVEL INTERVENSI DAN RENCANA PENGOBATAN


4.5.THE FUTURE OF GENE THERAPY :4.5.THE FUTURE OF GENE THERAPY :

Terapi Gen belum menjadi pengobatan routine dan Terapi Gen belum menjadi pengobatan routine dan hanya dimulai pada tahap pengembangan eksperimen hanya dimulai pada tahap pengembangan eksperimen Kebanyakan percobaan terapi gene saat ini ditujukan Kebanyakan percobaan terapi gene saat ini ditujukan lebih pada menemukan kemungkinan dan keamaan lebih pada menemukan kemungkinan dan keamaan daripada untuk mencari manfaat,daripada untuk mencari manfaat,Faktanya, terdapat hasil sejumlah percobaan yang Faktanya, terdapat hasil sejumlah percobaan yang membuktikan adanya manfaat klinik untuk pasienmembuktikan adanya manfaat klinik untuk pasienDilain pihak, tidak ada keraguan bahwa halangan Dilain pihak, tidak ada keraguan bahwa halangan teknologi akan dapat diatasi.teknologi akan dapat diatasi.


Adult and embryonic stemcellAdult and embryonic stemcell


General strategies for gene therapy for General strategies for gene therapy for tissue engineeringtissue engineering


Issues relating to successfull gene transferIssues relating to successfull gene transfer


Commonly used gene vectorCommonly used gene vector


Vector production process.Vector production process.


Strategy to combine gene therapy with nuclear Strategy to combine gene therapy with nuclear transfer and stem cell therapytransfer and stem cell therapy

An example to genetically modify skin fibroblast of an individual with a monogenetic disease, to correct the abnormality. The nucleus of the genetically corrected fibroblast is then transferred to an enucleated egg of an unrelated donor to generate corrected autologous pluripotent stem cells that can be differentiated and then transferred back to the patient.


G0 stage

Oocyte Donor

Koleksi sel donor

In vitro Maturation

Kulture Nuclear Transfer

+_

Enucleation

In vitro CulturePerkembangan embrio

elektrofusion

2 3 45

6

5-6 hari

7

1

8

9

Pasien

PasienPeminakan sel tunas terapeutik 6767KMA MUTASI KHROMOSOM GENEKMA MUTASI KHROMOSOM GENE

Adenovirus-mediated Adenovirus-mediated gene delivery into mouse gene delivery into mouse

spermatogonial stem cellsspermatogonial stem cells

Histological appearance of testes injected with AxCANLacZ at 7 days (A) or 4 weeks (B) after birth. Whole mounts of testes were stained 1 month after virus injection. (C–H) In vitro infection of immature testis cells (C and D), GS cells (E and F), and mGS cells (G and H) by AxCANEGFP. The cells were exposed to adenovirus overnight at 2.5 x105 pfu/ml (CandD) or 1.8 x105 10 pfu/ml (E–H) and EGFP fluorescence was examined 6 h (D) or 1 day (Fand H) after infection (I) Flow-cytometric analysis of immature testis cells 2 days after transduction of AxCANEGFP at 2.5x105 pfu/ml. EpCAM-positive spermatogonia cells showed EGFP fluorescence. Blackline, control Ig; redline, specific antibody.(J) Flow-cytometric analysis of GS cells 3 days after transduction of AxCANEGFP (K) Increase in GS cell number after adenovirus infection. After overnight infection, GS cells were cultured for 6 days. Although no significant difference in cell number was found at 6.0 x 103 pfu/ml, GS cells growth was inhibited at higher virus concentrations (P<0.05 by t test). (L) The intensity of EGFP signal decreased during a17-day culture. The cells were infected at 2.5x105 pfu/ml and passaged twice during this period. (Scale bars: 50m for C–H.) Takehashi et al. 2007; PNAS 104 (8):2596–2601


Diagram of the experimental Diagram of the experimental procedureprocedure

Testis cells from donor R26R mice were dissociated by trypsin digestion and infected in vitro by AxCANCre adenovirus. Cre-mediated recombination removed the neo cassette, and LacZ gene expression was initiated under the ROSA26 ubiquitous promoter. The infected cells were transplanted into infertile recipient testes. At 20 weeks after transplantation, recipient testes were mechanically dissociated, and spermatogenic cells were microinjected into oocytes to produce offspring. DNA from the offspring was analyzed by Southern blotting and PCR for integration of adenovirus.


PENUTUPPENUTUP

1.1. Mutasi dapat terjadi pada khromosom dan gene Mutasi dapat terjadi pada khromosom dan gene 2.2. dapat terjadi pada lokus, autosom dan seks dapat terjadi pada lokus, autosom dan seks

khromosom,khromosom,3.3. Kelainan dapat berupa kelebihan atau Kelainan dapat berupa kelebihan atau

kekurangan jumlah atau struktur khromosom kekurangan jumlah atau struktur khromosom atau geneatau gene

4.4. Kelainan dapat berupa kelainan anatomik dan Kelainan dapat berupa kelainan anatomik dan fungsi. fungsi.

5.5. Pendekatan Terapi Genetik dapat didekati dari Pendekatan Terapi Genetik dapat didekati dari berbagai tahap termasuk rekayasa genetik berbagai tahap termasuk rekayasa genetik dengan atau tanpa stem seldengan atau tanpa stem sel


DAFTAR RUJUKANDAFTAR RUJUKAN

1.1. Understanding Biology for Advanced Level Understanding Biology for Advanced Level Gleen and Susan Toole, Stanley Thorney Gleen and Susan Toole, Stanley Thorney Pub. Ltd, Cheltenham,UK 1999, Hal. 213-Pub. Ltd, Cheltenham,UK 1999, Hal. 213-2592.2592.

2.2. Biology, 5th Ed. Campbell,NA, Reece,JB, Biology, 5th Ed. Campbell,NA, Reece,JB, Mitchel,LG, Addison Wesley Longman, Inc., Mitchel,LG, Addison Wesley Longman, Inc., New York 1999. Hal. 913 – 935New York 1999. Hal. 913 – 935

3.3. Genetc in Medicine, Thompson & Thompson, Genetc in Medicine, Thompson & Thompson, Saunder, USA, 2004Saunder, USA, 2004

4.4. Introduction to Molecular Medicine, 3rd ed., Dennis Introduction to Molecular Medicine, 3rd ed., Dennis W Roos, Spriner,, New York, 2002W Roos, Spriner,, New York, 2002


Daftar Rujukan :Daftar Rujukan :

1.1. DP Snustad, MJ Simmons : Principle of Genetics, DP Snustad, MJ Simmons : Principle of Genetics, 3 rd edition, John Wiley & Sons, New York, 2003.3 rd edition, John Wiley & Sons, New York, 2003.

2.2. R.B. Mueller, ID Young.: Emery’s Elements of R.B. Mueller, ID Young.: Emery’s Elements of Medical Genetic, 10Medical Genetic, 10thth Edition, Edinburgh-London, Edition, Edinburgh-London, 1998.1998.

3.3. Sylvia S. Mader, Human Biology, 8Sylvia S. Mader, Human Biology, 8thth edition, Mc edition, Mc Graw Hill,New York, 2004.Graw Hill,New York, 2004.


mutasi

Documents

extra sex chromosome

myotonic dystrophy

gene therapy

gs cells

nuclear transfer

genetic testing

fmr1 gene

successive generations