INHERITANCE INTRODUCTION Transmission of certain gene disorder does not follow classic Mendelian principles. Diseases caused by tri-nucleotide repeat mutations. Disorders caused by mutations in mitochondrial genes. Disorders associated with genomic imprinting. Disorders associated with gonadal mosiacism In the fragile-X syndrome, expansions occur during oogenesis, In Huntington disease they occur during spermatogenesis. The mutations can be divided into two groups. The repeat expansions occur in noncoding regions,(fragile-X syndrome and myotonic dystrophy). Expansions occur in the coding regions (Huntington disease). MUTATIONS AFFECTING NON CODING REGIONS Expansions affect non coding regions Protein synthesis is suppressed Affect many systems Many non coding repeat disorders are characterized by intermediate- size expansions, or pre mutations That expand to full mutations in germ cells. It seems that during the process of oogenesis, but not spermatogenesis, premutations can be converted to mutations by triplet-repeat amplification
This explains the unusual inheritance
pattern: Grandsons incur the risk of inheriting a pre mutation from their grandfather that is amplified to a full mutation in their mothers' ova. When the trinucleotide repeats in the FMR1 gene exceed approximately 230, the DNA of the entire 5 region of the gene becomes abnormally methylated. Methylation extends upstream into the promoter region of the gene, resulting in transcriptional suppression of FMR1 The resulting absence of FMRP causes the phenotypic changes. Demonstration of an abnormal karyotype leads to the identification of this disorder. PCR based detection of repeats is the method of choice for diagnosis With Southern blot analysis between premutations can be made prenatally and postnatally. Feature unique to mtDNA is material inheritance . Ova contain numerous mitochondria in their cytoplasm. Spermatozoa contain few . mtDNA compliment of zygote is entirely derived from ovum. Mothers transmit mtDNA to all their offspring, male and female . Daughters and not sons transmit the DNA further to their progeny. Other features are as follows: All progeny of an affected male are normal All children male and female of the affected female manifest the disease Diseases associated with mitochondrial inheritance are rare. Many of them affect the neuromuscular system. Leber hereditary optic neuropathy is a prototype of this disorder. Neurodegenerative disease. Progressive bilateral loss of central vision. Visual loss first appears in ages 15 and 35 Complete blindness. Cardiac conduction defects. Minor neurological manifestations REFERENCES PATHOLOGIC BASIS OF DISEASE ROBBINS AND COTRAN (Pg:140 -142) thank you