Genetica umana - mutazioni monogeniche - Appunti

Genetic Inheritance

A A A A1 1 2 2| | | | | | |A A A A A A1 2 1 2 1 2A dominant Codominant A dominant1 2• Dominance, recessive, co-dominant inheritance are not absolutecategories: depends on the level of observation of the phenotype.– Clinical level: disease vs. no-disease (D vs. R)– Biochemical level: often co-dominant (e.g. many “genetic markers”).• Simplest model: full dominance of one allele.Autosomal dominant diseasesIIIIII– Affecteds usually have at least one affected parent (vertical transmission). Exceptions:IVnew mutations and reduced penetrance.– Affects both sexes– Transmitted by either sex– A child of an affected and an unaffected individual usually has a 50% chance of beingaffected (If the disease is rare, almost all affecteds are heterozygotes)– Normal children of an affected parent have only normal offpring (as well as furtherdescendants). Exception: reduced penetrance.Some complications…• New mutation:–

Occasionally an affected person is detected with no prior family members affected.

• In benign conditions, most cases will be transmitted.
• In conditions seriously affecting reproduction an increasing proportion will appear as new mutations: e.g. ~ 80% of achondroplastic dwarfs are due to new mutations
• Late age of onset (Age-dependent penetrance)
  • In HD by age 45 only about 50% of the individuals carrying the mutation have manifested the disease. By age 70, almost all will have manifested it.
  • This can lead to the presence of unaffected carrier individuals which make the disease skip a generation.
• Expressivity
  • Is the extent to which a trait is manifest in an individual. e.g. Neurofibromatosis type 1 (NF1) is a dominant disease with complete penetrance but with highly variable clinical manifestations even within a family.

Autosomal Recessive Diseases

IIIIIIIV - Affecteds within a single sibship ("horizontal" transmission) - Affected

individuals are usually born to unaffected (carrier) parents – With a 1/4 probability of being affected. – Increased probability of parental consanguinity – Affects either sex.

Autosomal Recessive inheritance

• Consanguinity in recessive disorders:
  • These diseases often appear among the progeny of consanguineous matings, particularly for the rarer disorders (e.g. in xeroderma pigmentosa about 25% of cases come from first cousin marriages).
• Pseudodominance: offspring of the mating between an affected individual and a carrier have a 1/2 chance of being affected.
• Compound heterozygotes: at the molecular level there can be a series of recessive mutants.
• Genetic heterogeneity: the same disorder can be caused by mutations in different genes. Offspring of affected individuals carrying different mutant genes are phenotypically normal (e.g. sensorineural deafness)

Mendelian pedigree patterns further complications non penetrance (NP) Mendelian pedigree

patterns

further complications

variable expression

Mendelian pedigree patterns

further complications

imprinting

Mendelian pedigree patterns

further complications

germinal mosaicism

IIIIII III- 1 new mutation

II-1 new mutation

II-1 germline mosaicism

I-2 germline mosaicism

Mendelian pedigree patterns

further complications

anticipation = phenotypic severity increases

with each generation

IIIIII

Age of onset grandmother < father

Affected fetus diagnosed prenatally

Mendelian pedigree patterns

molecular pathology

one gene

genetic variability:severity of phenotype depends upon

type of mutation

different mutations cause different(related) syndromes

Mendelian pedigree patterns

molecular pathology

one gene

loss of function vs gain of function

RET gene = receptor

lof - Hirschsprung’s disease

gof - fam. medullary thyroid ca

MEN2

Mendelian pedigree patterns

molecular pathology

one phenotype, several genes

profound deafness

compound heterozygosity

Ereditarietà non Mendeliana

Ereditarietà Mitocondriale

Malattie da

1. tripletteImprintingDisomia UniparentaleEreditarietà Digenica
2. MitochondrialDNA•~ 16.5 kb on adouble-strandedcircular molecule•encodes:22 tRNAs2 rRNAs13 polypeptides(subunits of enzymes)involved in OXPHOS)
3. Mitochondrial DNA• Several hundred mitochondria per cell• 5-10 mtDNA molecules per mitochondrion• mutation rate 10x that of nuclear DNA
4. target size of coding DNA!largeprotected by histones!not many more rounds of replication that!undergoesnuclear DNA
5. Mitochondrial DNA• Nuclear genes:other 74 polypeptides of the OXPHOS!Encodecomplexthe integrity and quantity of mtDNA!Affect of these genes are inherited in!Defectsclassical Mendelian modes• Autosomally transmitted deletions in mtDNA• AR mtDNA depletion syndrome
6. Maternal Transmission• Diseases due to defects in themitochondrial genome are transmitted asthe mitochondria themselves - from themother to all of her children, regardless ofsex.• Males inherit mtDNA from their

• aumento graduale (espansione) del numero delle triplette
• nella populazione normale, il numero delle ripetizioni è variabile, ma stabile
• il primo momento è la formazione della "premutazione" che è associata a un fenotipo normale ma è instabile
• la premutazione poi si espande in una successiva generazione assumendo una lunghezza maggiore e un'instabilità elevata
• l'anticipazione è una caratteristica dell'espansione delle triplette

• >75 premutation
• 45-75 myotonic protein kinase gene normal 5-30 (CTG)n

• X-linked
• si verifica in ~1,250 maschi ed è la seconda causa più comune di ritardo mentale
• associata a ritardo mentale da moderate a severo e spesso a sviluppo ritardato e comportamento autistico
• la malattia mostra anticipazione
• aumenta della

“penetranza” nelle generazioni successive• la trasmissione tramite donne può aumentare il rischio per le•generazioni successive• le donne eterozigoti e I maschi con premutazione possonomostrare un lieve difetto cognitivo• causata da mutazioni nel gene FMR-1 espresso nel cervello enei testicoli• il gene normale ha in posizione 5’-UTR un numero di tripletteCGG che varia nella popolazione generale tra le 6-55 copie•I pazienti hanno un numero di triplette maggiore, fino a diversemigliaia, che impedisce la trascrizione del mRNAStructure and inheritance of CGG repeatsin fragile X syndromeaffected >200premutation 55-200normal 6- FMR-1 gene55 (CGG)nAtrofia muscolare spinale e bulbare (Kennedy)• X-linked; rara• degenerazione del motoneurone a esordio tardivo associata aritardo mentale e non responsività agli androgeni• causeta da mutazioni nel gene del recettore degli androgeni• il gene normale ha in posizione

5’-UTR un numero di triplette CAG che varia nella popolazione generale tra le 13-28 copie repeats• I pazienti hanno un numero di triplette maggiore, fino a 39-60• le ripetizioni CAG sono tradotte in un tratto di poliglutamine nella proteina• la malattia mostra anticipazione, ma la severità non è correlata al numero delle triplette

Structure and inheritance of CAG repeats in spinal and bulbar muscular atrophy affected 39-60 normal 13-28 androgen receptor gene(CAG) n(Gln) n

Chorea di Huntington• Malattia autosomica dominante• Età di esordio variabile (da giovanile a forme dell’adulto)• associata a movimenti involuntari (chorea), disturbi del comportamento e deficit cognitivo• causata da mutazioni nel gene IT15 (a funzione non ben conosciuta)• il gene normale ha in posizione 5’-UTR un numero di triplette CAG che varia nella popolazione generale tra le 11-35 copie repeats• I pazienti hanno un numero di triplette

maggiore(>35 repeats)