GENETIC DISORDERS

Upik A. Miskad

Basic of genetic sciences

Gambar cel

Komponen kromosom

HUMAN GENETIK ARCHITECTUREGenetika:mempelajari satu atau beberapa gen dan efek fenotipik

Genomika:studi tentang semua gen dan interaksinya

Diperkirakan kurang dari 2% yg diketahui of the human genome encodes proteins

Manusia mempunyai 20 ribu hingga 25 ribu gen yg mengkode proteinPerubahan dari setiap gen akan meberikan gangguan genetik

Figure 5-1 Generation of microRNAs and their mode of action in regulating gene function. Pri-miRNA, primary microRNA transcript; pre-miRNA, precursor microRNA; RISC, RNA-induced silencing complex.Downloaded from: StudentConsult (on 6 February 2010 09:43 AM) 2005 Elsevier

MUTASI Perubahan permanent pada DNA.Mutasi yang mengenai sel germinativum diwariskan dan dapat memberikan penyakit herediter.Mutasi dalam sel somatik, tidak dapat menyebabkan penyakit herediter tetapi penting sebagai pada kejadian kanker dan kelainan malformasi kongenital.

POINT MUTATION Subtitusi satu basa nukleotida oleh basa yang lainAkibatnya: protein produk satu asam amino digantikan oleh asam amino lainMengubah arti kode genetik

JENIS MUTASI:SUBTITUSI (SILENT,MISSENSE,NONSENSE)

FRAMESIHIFT (DELESI,INSERSI)

MENDELIAN DISORDERTerjadi mutasi hanya pd satu gen.Diperkirakan setiap individu membawa 5 sampai 8 gen yg mengalami gangguanSebagian besar bersifat resesifMutasi pd satu gen biasanya mengiuti satu dari 3 pola pewarisan 1.Autosom dominan 2.Autosom resesif 3.X linked

POLA TRANSMISI GANGGUAN GEN TUNGGALAUTOSOMAL DOMINAN DISORDERAUTOSOMAL RESESIF DISORDERX-LINKED

GANGGUAN AUTOSOM DOMINANDimanifestasikan dalam keadaan heterozigotSetidaknya satu dari kedua orang tua sebagai pembawaTimbulnya gambaran klinik lebih lambat usia dewasa Beberapa individu yg menderita kedua orangtua yg normal

Autosomal Dominant Dominant conditions are expressed in individuals who have just one copy of the mutant allele. The pedigree on the right illustrates the transmission of an autosomal dominant trait. Affected males and females have an equal probability of passing on the trait to offspring. Affected individual's have one normal copy of the gene and one mutant copy of the gene, thus each offspring has a 50% chance on inheriting the mutant allele. As shown in this pedigree, approximately half of the children of affected parents inherit the condition and half do not. Autosomal Dominant

AUTOSOMAL RESESIVEMulai timbul pd usia awal kehidupanLebih sering terjadiGambaran klinis cenderung seragamGen yg mutasi yg mengkode protein enzim

Autosomal Recessive Recessive conditions are clinically manifest only when an individual has two copies of the mutant allele. When just one copy of the mutant allele is present, an individual is a carrier of the mutation, but does not develop the condition. Females and males are affected equally by traits transmitted by autosomal recessive inheritance. When two carriers mate, each child has a 25% chance of being homozygous wild-type (unaffected); a 25% chance of being homozygous mutant (affected); or a 50% chance of being heterozygous (unaffected carrier). Affected individuals are indicated by solid black symbols and unaffected carriers are indicated by the half black symbols.

X-LINKED DISORDERSemua sex-linked disoreder X-linked hampir semua resesifSejumlah kecil kondisi klinik baikCiri gangguan tersebut :Laki-laki yg terkena tidak menurunkan ke anak laki-lakinya, tetapi semua anak perempuannya carrierAnak laki-laki dr wanita heterozigot terkena 50%Hanya sedikit X-linked dominant

X-linked Recessive X-linked recessive traits are not clinically manifest when there is a normal copy of the gene. All X-linked recessive traits are fully evident in males because they only have one copy of the X chromosome, thus do not have a normal copy of the gene to compensate for the mutant copy. For that same reason, women are rarely affected by X-linked recessive diseases, however they are affected when they have two copies of the mutant allele. Because the gene is on the X chromosome there is no father to son transmission, but there is father to daughter and mother to daughter and son transmission. If a man is affected with an X-linked recessive condition, all his daughter will inherit one copy of the mutant allele from him.

X-linked Dominant Because the gene is located on the X chromosome, there is no transmission from father to son, but there can be transmission from father to daughter (all daughters of an affected male will be affected since the father has only one X chromosome to transmit). Children of an affected woman have a 50% chance of inheriting the X chromosome with the mutant allele. X-linked dominant disorders are clinically manifest when only one copy of the mutant allele is present.

COMPLEX MULTIGENIC DISORDERS Variasi bentuk gen + faktor lingkungan penyakit Polimorfism = satu varian genetik mempunyai paling sedikit 2 alel, & muncul pada paling kurang 1 % populasiCOMMON VARIANT HYPOTHESIS :Penyakit genetik timbul ketika terdapat banyak polmorfism dengan efek & penetrasi yang rendah diwariskan.

COMPLEX MULTIGENIC DISORDERS Variasi bentuk gen + faktor lingkungan penyakit Polimorfism = satu varian genetik mempunyai paling sedikit 2 alel, & muncul pada paling kurang 1 % populasiCOMMON VARIANT HYPOTHESIS :Penyakit genetik timbul ketika terdapat banyak polmorfism dengan efek & penetrasi yang rendah diwariskan.

C/. DM type II menandai penyakit ini harus diperhatikan beberapa faktor : family clustering eksklusi mendelian model transmisi kromosom

TERIMA KASIH

TERIMA KASIH

LOSS OF FUNCTION MUTATIONSTergantung pd tipe protein yg dipengaruhi1.mutasi yg mempengaruhi protein enzim heterozigot normal2.Mutasi yg mempengaruhi protein non-enzim : Melibatkan jalur regulasi komplex metabolik (cth:familial hipercholestrolemia) Melibatkan protein struktural utama( cth :kolagen dan unsur sitoskeletal membran ertrosit)

MEKANISME BIOKIMIA1. Loss of function mutation

2. Gain of function mutation

GAIN-OF-FUNCTIN-MUTATIONSProduk protein mutasi dari alel mutan memperoleh difat baru yg tidak normal (wild-type protein)

HUMAN GENETIK

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