-Mitochondrial disorder

-1st

-missense mutation

-maternal inheritance, homoplasmic

-mitochondrial disorder

-myoclonic seizure 'bow down'

-point mutation

-maternal inheritance, heteroplasmic

-mitochondrial disorder

-maternal inheritance, heteroplasmic

-point mutation

KSS Kearns-Sayre syndrome

-mitochondrial disorder

-heteroplasmic

-large deletions

-Mitochondrial disorder

-elevated lactic acid

-mtDNA mutation

-MANY causes (big interlocking circle graph)

Mosaicism

Presence in an individual of at least 2 cell lines which differ genetically (genotype or karyotype) but are derived from a single zygote

Somatic Mosaicism

-mutation in non-germ cells

-affect morphogenesis/embryonic dev

-post zygotic event

-NF 1 with cafe-au-lait spots

-MANY cancer types

Germline mosaicism

Germline contains allele/mutation not present in somatic cells

-parents who are phenotypically normal and no family history have MORE THAN ONE affected chid

Osteogenesis imperfecta

-Germline mosaicism

-autosom DOMINANT

Neurofibromatosis 1

-germline mosaicism

-autsom. dominant

-cafe-au-lait spots

Duchenne muscular dystrophy

-germline mosaicism

-X-linked recessive

Genomic imprinting

-differential expression of alleles of a gene depending on whether inherited from father or mother

-different methylation of genes during male/female gametogenesis--transciptional inactivation

-ABSENCE OF GENES FROM 1 PARENT RESULTS IN ABNORMAL DEV.

ie: Hydatidiform moles, ovarian tetratomas

Prader-Willi syndrome

-hypotonia, failure to thrive in infancy

-deletion of Paternal chrom 15

-to be normal there must be functional PWS critical region active on paternal 15; maternal is normally silenced by methylation

-maternal uniparental disomy: can cause PWS ~30%

-mutation in imprinting center causes abnormal methylation in the paternal 15

Uniparental disomy

-presence of 2 copies of a specific chromosome inherited from a single parent, instead of normal biparental inheritance

Isodisomy

-both copies of the chrom are identical

-due to error in MEIOSIS II

Heterodisomy

-both copies of the chromosome from the same parent BUT THEY ARE DIFFERENT

-error in MEIOSIS I

Angelman syndrome

-"happy puppet", mental retardation

1. microdeletion of MATERNAL chrom15

--paternal 15 normally methylated/silenced

2. paternal uniparental disomy, so there is no copy of maternal 15

3. biparental inheritance of chrom 15 with mutations in AS gene, abnormal methylation due to imprinting center, or silencing of UBE3A gene

Beckwith-Wiedmann syndrome

-uniparental disomy chrom11

-excess paternal

-OR loss maternal contribution chrom11

Trinucleotide/triple repeat expansion

-triple repeats are normally stably transmitted

-expansion of triplet repeat sequences are unstable-->diseases

-Mechanisms causing disease for triplet repeat expansion

1) polyglutamine tract: CAG

2) nonpolyglutamine tract

    -hypermethylation

    -interaction w/ RNA binding proteins

-genetic disease occurring at progressively earlier age of onset with increasing severity in successive generations

-CAUSE: expansion of triplet repeats

-triplet repeat expansion

X linked

unstable CGG in FMR1 of X chromosome

mutation= >200 repeats

-triplet repeat expansion

-autosomal DOMINANT

-not just muscular, systemic disease

-CTG repeats

-most severe when MATERNAL inheritance

-triplet repeat disease

-autosomal DOMINANT

-100% penetrance

-memory loss

-CAG repeat expansion

-juvenile hd PATERNAL inheritance

-mitochondrial inheritance

-heterogeneity in proportion non-mutant and mutant mitochondrial DNA

-mitochondrial inheritance

-pure mutant OR normal mtDNA

replicative segregation

-mitochondrial DNA
-mtDNA replicates separately from nDNA

    -mtDNA 10X greater rate of mutation than nDNA

common clinical presentation mitochondrial disorders

CNS:

eyes:

muscle:

endocrine:

CNS: seizures, myoclonus

Eyes: retinitis pigmentosa, optic atrophy

Muscle: red ragged fibers

Endocrine: diabetes mellitus

3 types of mitochondrial DNA mutations

1) missense mutation in coding

2) point mutation in tRNA/rRNA

3) rearrangments generate deletions/duplications