MUTASI

Kiagus Muhammad Arsyad

Bagian Biologi Kedokteran dan Andrologi

Fakultas Kedokteran UNSRI

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TUJUAN PEMBELAJARAN
Agar mahasiswa mampu mengetahui dan memahami tentang : 1. Mutasi 2. Penyebab Mutasi 3. Penyakit akibat mutasi 4. Terapi genetik untuk berbagai penyakit genetik.

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MATERI PEMBELAJARAN
1. 2. 3. 4. 5. Pendahuluan Penyebab Mutasi Macam Mutasi Penyakit akibat mutasi Terapi genetik

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Menurut Biologi, MUTASI adalah setiap perubahan fisik pada materi genetik dari suatu organisme. Hampir sebagian besar kasus terjadi pada DNA atau RNA didalam inti sel. Pada organisme multicellular ada 2 macam kelas yaitu : 1. Germ line mutation, dan 2. Somatic Mutation.
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Faktor penyebab: 1. Internal, penyebab adalah errors pada reproduksi materi genetik. 2. External, yang sering radiasi ultraviolet, chemical mutagens, atau parasitic organisms (virus atau bacteria).
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ENVIRONMENT :
1. INTERNAL 2. EXTERNAL

GENE

MUTATION

POLYMORPHISM

ABNORMAL PHENOTYPE

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Inheritance
Prevention of inherited traits: Decision not to reproduce Fetal destruction Abortion

Environmental exposure
Reduction in mutagens

Radiation and environmental exposure: Biological Physical Socioeconomic

Genetic mutations and polymorphisms Gene therapy Genetic risks To prevent second hit Disease risk Environmental risk Mutagens

Behavioral changes: Smoking Diet Exercise Drugs & alcohol

Other measures: Chemoprevention Early detection Population screening Removal of target organs

Disease KMA MUTASI KHROMOSOM GENE

Ada 2 macam Mutasi : 1. Mutasi pada Gene (Point Mutation) 2. Mutasi pada khromosom

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DEFINISI

Perubahan Susunan Nukleotida DNA

JENIS

Mutasi Titik Delesi Insersi

t.a.a Fungsi Fungsi Tak berfungsi (inactivated) Sel benih Peny. Keturunan Sel Somatik Kanker DNA Mitokondria (menimbulkan penyakit yang diwariskan garis keturunan ibu)
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AKIBAT

LOKASI

1 Klas mutasi

1.1 Deletion mutations 1.2 Insertion mutations 1.3 Substitution mutations 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
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2 Subklas Mutasi

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Crossing over

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Non Dysjunction

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Extra sex chromosome

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Extra sex chromosome

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KELAINAN SEKS KHROMOSOM

Kelainan seks khromosom Khromosom Y : lengan p & q, Y linked gen, TDF, SRY, AZFa,AZFb,AZFc,DAZ Khromosom X : XIST, Xi Macam kelainan seks khromosom : Pria = 47,XXY,48XXXY, 47XYY, XX males, Wanita= XO,Trisomy X, XY females, Androgen insensitivity
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1.

2. 3.

4.

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KHROMOSOMAL ABNORMALITY SYNDROME

1. 2. 3. 4. 5. 6. Down Syndrome. Trisomy 18 Syndrome, Trisomy 13 syndrome, Trisomy 8 Syndrome, Trisomy 9 Mosaic syndrome, Triploidy Syndrome and Diploid/Triploid Mixoploidy Syndrome, 7. Deletion 2p syndrome 8. Duplication 3q syndrome, 9. Deletion 4p syndrome, 10. Duplication 4syndrome,
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KHROMOSOMAL ABNORMALITY SYNDROME

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

22. Cat-eye syndrome 23. XYY Syndrome, 24. XXY Syndrome, Klinefeleter syndrome, 25. XXXY and XXXXY Syndrome, 26. XXX and XXXX syndrome 27. XXXXX syndrome 28. XO syndrome
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Table 11.1

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4. MUTASI DINAMIK
Penyakit yang timbul akibat mutasi yang khas yaitu Mutasi dinamik dimana suatu elemen heritable yang tidak stabil dimana probalitas dari mutasi tergantung dengan jumlah kopi yang bermutasi. Karena itu produk replikasi dari mutasi dinamik akanberbeda dari pewarisnya (predecessor). Mutasi ini dicirikan dengan pengulangan sekuens pendek berkali kali, menimbulkan berbagai penyakit termasuk Trinucleotide repeat disorders.
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4. MUTASI DINAMIK
Robert I. Richards and Grant R. Sutherland menyebut phenomena ini, dalam kerangka dynamical genetics, sebagai dinamika mutasi Ekspansi Triplet disebabkan oleh slippage semasa replikasi DNA. Karena pengulangan sekuens DNA pada daerah struktur 'loop out' mungkin terbentuk semasa replikasi DNA memungkinkan disintesanya penambahan pasangan basa complementary base diantara pita ortu dan anaknya

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4. MUTASI DINAMIK
1. 2. 3. 4. 5. 6. 7. 8. 9.
Contoh Mutasi dinamik : Fragile X syndromes Huntington's Chorea Myotonic dystrophy Spinobulbar muscular atrophy Spinocerebellar ataxia type 3 Friedreich ataxia Ocularpharyngeal muscular dystrophy Progressive myoclonus epilepsy Creutzfeldt-Jakob disease
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1. FRAGILE X SYNDROME
Fragile X syndrome, atau Martin-Bell syndrome, adalah suatu sindroma genetik dengan manifestasi beragam pada ciri2 fisik, intelektual, emosional dan gambaran perilaku dari ringan sampai berat. Fragile X syndrome adalah bentuk retardasi mental yang disebabkan oleh mutasi gen pada khromosom X. disebut demikian karena lengan panjang khromosom X tampak seperti pecah/retak

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Penyebab Fragile X syndrome

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

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Transmisi fragile X
Males with the fragile X cannot transmit it to any of their sons (since males contribute a Y chromosome, not an X, to their male offspring), but will transmit it to all of their daughters, as males contribute their X to all of their daughters. Females carrying one copy of the fragile X can transmit it to their sons or daughters; in this case each child has a 50% chance of inheriting the fragile X. Sons who receive the fragile X are at high risk of intellectual disability. Daughters who receive the fragile X may appear normal or they may be intellectually disabled, usually to a lesser degree than boys with the syndrome. The transmission of fragile X often increases with each passing generation. This seemingly anomalous pattern of inheritance is referred to as the Sherman paradox.
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Physical Phenotype
1. Prominent ears 2. Long face (vertical maxillary excess) 3. High-arched palate (related to the above) 4. Hyperextensible finger joints 5. Double-jointed thumbs 6. Flat feet 7. Soft skin 8. Larger testicles in men (macroorchidism) 9. Low muscle tone
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Diagnosis
Fragile X syndrome was originally diagnosed by culturing cells in a folate deficient medium and then assessing the cultures for X-chromosome breakage by cytogenetic analysis of the long arm of the X chromosome. This technique proved unreliable for both diagnosis and carrier testing. The fragile X abnormality is now directly determined by analysis of the number of CGG repeats and their methylation status using restriction endonuclease digestion and Southern blot analysis.

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2. HUNTINGTONS DISEASES
Huntington's disease or chorea (HD) is an incurable neurodegenerative genetic disorder that typically manifests itself first in middle age. It is the most common genetic cause of abnormal involuntary writhing movements called chorea. It is much less common in people of Asian or African descent than in people from Western Europe
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PENYEBAB H.D.
The disease is caused by a mutation on either of the two copies of a specific gene, located on an autosomal chromosome. As the mutation is dominant, each child of an affected parent has a 50% chance of inheriting the disease. In rare situations where both parents have an affected gene, or either parent has two affected copies, this chance is greatly increased.

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Tanda dan simptom

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

Reported prevalences of behavioral and psychiatric symptoms in Huntington's disease[10] Irritability3873% Apathy3476% Anxiety3461% Depressed mood3369% Obsessive and compulsive10 52%Psychotic311%
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PEWARISAN
Huntington's disease has autosomal dominant inheritance, meaning that an affected individual typically inherits a copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected parent. In this type of inheritance pattern, each offspring of an affected individual has a 50% chance of inheriting the mutant allele and therefore being affected with the disorder (see figure). This probability is sex-independent.

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Diagnosis
Diagnosis of the onset of HD can be made following the appearance of physical symptoms specific to the disease. Genetic testing can be used to confirm a physical diagnosis if there is no family history of HD. Even before the onset of symptoms, genetic testing can confirm if an individual or embryo carries an expanded copy of the HTT gene that causes the disease. Genetic counseling is available to provide advice and guidance throughout the testing procedure, and on the implications of a confirmed diagnosis. These implications include the impact on an individual's psychology, career, family planning decisions, relatives and relationships. Despite the availability of pre-symptomatic testing, only 5% of those at risk of inheriting HD choose to do so.
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Differential diagnosis
Although HD accounts for ninety percent of the cases of chorea caused by genetic disorders, and an observational diagnosis for someone with typical symptoms and a family history of the disease is usually correct, a genetic test is required to rule out other disorders.[5][39] Most of these other disorders are collectively labelled HD-like (HDL).[39] The causes of most of these HDL diseases are unknown, but those with known causes are due to mutations in the prion protein gene (HDL1), the junctophilin 3 gene (HDL2), a recessively inherited HTT gene (HDL3 only found in one family and poorly understood), and the gene encoding the TATA box-binding protein (HDL4/SCA17).[39] [edit]
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3. MYOTONIC DYSTROPHY
Myotonic dystrophy (dystrophia myotonica, DM) is a chronic, slowly progressing, highly variable inherited multisystemic disease that can manifest at any age from birth to old age. It is characterized by wasting of the muscles (muscular dystrophy), posterior subcapsular iridescent cataracts (opacity of the lens of the eyes), heart conduction defects, endocrine changes and myotonia (difficulty relaxing a muscle). Most notably, the highly variable age of onset decreases with successive generations. Thus the disease shows at an earlier age in successive generations, a phenomenon termed anticipation. There are two classifications of DM, each having different associated symptoms.
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Klasifikasi
Myotonic dystrophy is the most common form of muscular dystrophy allowing adult survival and the second most common form of any skeletal muscle disease after Duchenne muscular dystrophy. There are currently two known types of adult onset DM, both identifiable by DNA analysis: Myotonic dystrophy type 1 (DM1), also known as Steinert's disease. DM1 has a congenital form that can severely affect babies and a childhood onset form. Myotonic dystrophy type 2 (DM2), commonly referred to as PROMM or proximal myotonic myopathy. 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 of unusual phenotypes and is believed to be underdiagnosed. Other forms of myotonic dystrophy (DM3, DM4, DMX) are currently suspected by researchers to exist.[citation needed] One recent case was proposed as a candidate for the "DM3" label,[1] but was later characterized as a form of Paget's disease.[2][3]

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Perbedaan DM1 dan DM2

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

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Simptom
Presentation of symptoms varies considerably by form (DM1/DM2), severity and even unusual DM2 phenotypes. DM1 patients often present with myotonia, disabling distal weakness and severe cognitive problems. DM2 patients commonly present with muscle pain, stiffness, fatigue, or the development of proximal lower extremity weakness (Day & al, 2003). The characteristic pattern of weakness is different for DM1 and DM2: In DM1, it is noted in face and jaw muscles, the drooping of the eyelids (ptosis), weakness of the neck muscles, hands and lower legs. In DM2, the weakness is more evident in proximal muscles, those closer to the trunk of the body: neck, shoulders, hip flexors and upper legs.
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Genetik
DM is a genetic condition which is inherited in an autosomal dominant pattern, meaning that inheriting a mutant gene from one parent will result in the condition. There is a 50% chance of inheriting DM from an affected parent. DM is one of several known trinucleotide repeat disorders. Certain areas of DNA have repeated sequences of two or three nucleotides.

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Diagnosis
The diagnosis of DM1 and DM2 can be difficult and may be delayed due to the large number of neuromuscular disorders, most of which are very rare. Neuromuscular disorders can cover more than 40 different diseases and additional forms of these bring the number of distinct disorders close to 100.

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

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

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4.TERAPI GEN
1. Pendahuluan 2. Status Terapi gene saat ini 3. Pertimbangan khusus untuk Terapi gene 4. Rencana Terapi 5. Masa Depan Terapi Gene

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4.1. Pendahuluan
Terapi Genetik adalah penghantaran materi genetik kedalam sel untuk mengembalikan fungsi sel. Materi genetik yang diberikan dapat berupa : 1. deoxyribonucleic acid (DNA) atau 2. RNA, atau 3. Protein yang berperan pada sejumlah kasus.

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4.1. Pendahuluan
Perubahan fungsi sel bisa menambah atau mengurangi jumlah protein asal yang dihasilkan, atau produksi protein asing. Pemberian materi genetik bisa dilakukan dengan microinjection, atau carrier yang berinteraksi dengan membrane sel atau terikat protein membrane sebagai bagian pintu masuk ke dalam sel.
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4.1. Pendahuluan
Polynucleotida bisa berbentuk pita tunggal atau ganda, dan bisa diberikan code untuk pesan, atau tidak (sebagaimana pada kasus pemberian antisense gene). Walaupun lokasi sel pada waktu pemberian gene tidak dibatasi. Sel sisa bagian dari makhluk hidup, bisa berupa kultur pada piringan, atau bisa diambil dari organisme, ditransfeksikan, dan dipindahkan ke dalam organisme yang sama atau berbeda pada saat diperlukan.

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4.1. Pendahuluan
Terapi Gene berkembang setelah perkembangan teknologi recombinant DNA dan berkembang menggunakan teknik pemindahan gene dengan memakai carier viral dan nonviral. Teknik teknik ini telah berhasil baik pada pengobatan penyakit dan berkembang sampai tahap uji klinik yang juga sukses.

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4.2. STATUS TERAPI GENE SAAT INI

Tujuan terapi gene adalah untuk menambah, memperbaiki , atau memblok expresi genes pada pengobatan penyakit yang inherited, juga non-inherited. Macam terapi : 1. Somatic versus Germ line gene therapy 2. Ex Vivo versus in Vivo gene therapy
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4.3. PERTIMBANGAN KHUSUS UNTUK TERAPI GENE

1. Penambahan Gene, 2. Terapi bloking dan reparasi Gene (antisense, ribozyme, targeted homologous recombination), Metoda: 1. Non viral (liposomes, Naked DNA), 2. Viral (retrovirus, Adenovirus, Adenoassociated virus, others vectors)
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4.4. RENCANA TERAPI :

Penyakit genetik dapat diobati pada berbagai level sesuai tahap mutasi dari gene. Pengobatan pada level of clinical phenotype mengikutkan semua intervensi medik dan bedah, Yang penting pasien diberi edukasi tentang : a. penyakit genetik, b. keberhasilan, c. komplikasi, d. dampak genetik terapi, dan e. ketidaknyamanan pengobatan.

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LEVEL INTERVENSI DAN RENCANA PENGOBATAN

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4.5.THE FUTURE OF GENE THERAPY :

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

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Adult and embryonic stemcell

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General strategies for gene therapy for tissue engineering

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Issues relating to successfull gene transfer

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Commonly used gene vector

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Vector production process.

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Strategy to combine gene therapy with nuclear transfer 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 pluripotent KMA MUTASIautologous KHROMOSOM GENE stem cells that can be 66 differentiated and then transferred back to the patient.

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Koleksi sel donor
G0 stage

Kulture

Pasien

2
In vitro Maturation

3
Enucleation

Nuclear Transfer

5
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Oocyte Donor

elektrofusion

6
Perkembangan embrio
In vitro Culture

7
5-6 hari

8 9 Pasien
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Peminakan sel tunas terapeutik

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Adenovirus-mediated gene delivery into mouse spermatogonial 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. (CH) 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 (EH) 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. EpCAMpositive 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 CH.) Takehashi et al. 2007; PNAS 104 (8):25962601 KMA MUTASI KHROMOSOM GENE 68

Diagram of the experimental procedure

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.

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PENUTUP
1. Mutasi dapat terjadi pada khromosom dan gene 2. dapat terjadi pada lokus, autosom dan seks khromosom, 3. Kelainan dapat berupa kelebihan atau kekurangan jumlah atau struktur khromosom atau gene 4. Kelainan dapat berupa kelainan anatomik dan fungsi. 5. Pendekatan Terapi Genetik dapat didekati dari berbagai tahap termasuk rekayasa genetik dengan atau tanpa stem sel
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DAFTAR RUJUKAN
1. Understanding Biology for Advanced Level Gleen and Susan Toole, Stanley Thorney Pub. Ltd, Cheltenham,UK 1999, Hal. 2132592. Biology, 5th Ed. Campbell,NA, Reece,JB, Mitchel,LG, Addison Wesley Longman, Inc., New York 1999. Hal. 913 935 Genetc in Medicine, Thompson & Thompson, Saunder, USA, 2004 Introduction to Molecular Medicine, 3rd ed., Dennis W Roos, Spriner,, New York, 2002
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2.

3. 4.

Daftar Rujukan :
1. DP Snustad, MJ Simmons : Principle of Genetics, 3 rd edition, John Wiley & Sons, New York, 2003. 2. R.B. Mueller, ID Young.: Emerys Elements of Medical Genetic, 10th Edition, Edinburgh-London, 1998. 3. Sylvia S. Mader, Human Biology, 8th edition, Mc Graw Hill,New York, 2004.

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