Week 5- Mitochondrial inheritance/ Mltifactorial inheritance/ mutation types and inheritance pattern Flashcards
Mitochondrial inherited disorders
1) DM type 1
2) 1555A> G associated deafness (Sensoeineural hearing loss)
3) LHON - Leber Hereditary Optic Neuropathy
4) Leigh syndrome
In Mitochondrial Inheritance
* Mitochondrial DNA is ———— inherited
* ——- sexes equally affected
* Only —— transmission of disease (no male transmission at all)
- Mitochondrial DNA is maternally inherited
- Both sexes equally affected
- Only maternal transmission of disease (no male transmission at all)
———– : Mitochondria contain mix of mutant and wild-type mtDNA, Proportion of mutant mtDNA differs in different tissues or even cells of same tissue
Heteroplasmy
———-: * Mutant mtDNA are “selected out” with repeated mitoses, but accumulate in tissues not undergoing mitoses (e.g. neurons, muscles)
Replicative Segregation
——– : Symptoms develop only when mutant mtDNA reaches certain threshold (usually high, >90%).
Threshold depends on energy metabolism of tissue
Thershold effect
——— : Mitochondrial genetic in oogenesis that permits only a small subset of maternal mtDNA genomes to be effectively transmitted to progeny
Bottleneck effect
Homoplasmic mtDNA mutations are transmitted to ?
Maternal offspring
(however, not all offsprings will manifest the disease)
Key systems involved in mitochondrial Disease
1) CNS –> seizures, ataxia, dementia
2) Skeletal muscle –> myopathy
3) CVS -> cardiomyopathy
4) Liver –> hepatic dysfunction
5) Pancreatic islets -> diabetes mellitus
6) Hearing and vision -> Sensorineural deafness, optic atrophy, retinopath
**
Mitochondrial DNA (mtDNA) deletion Syndromes (Overlapping phenotypes)
1) Kearns-Sayre syndrome
2) Pearson syndrome
3) Progressive External Ophthalmoplegia (PEO)
**
CF of Kearns-Sayre syndrome
Triad:
1) Onset <20 yrs
2) Pigmentary retinopathy
3) Progressive external ophthalmoplegia (PEO)
Plus at least one of
* Cardiac conduction defect
* CSF protein >100mg/dL
* Cerebellar ataxia
* mtDNA deletion syndrome
Non-Syndromic Mitochondrial deafness
(1555A>G associated deafness) is caused by mutations in?
MT-RNR1-Related Hearing Loss (gene for 12S rRNA)
MOI of 1555A>G associated deafness
Mitochondrial inheritance
(CF: hearing loss)
Penetrance of 1555A> G associated hearing loss
* ——% penetrance with exposure to Aminoglycoside abx (non-dose related)
* Reduced penetrance without exposure (about —-% by age 65 years)
- 100% penetrance with exposure (non-dose related)
- Reduced penetrance without exposure (about 80% by age 65 years
The most frequent mitochondrial disease presentation in early childhood?
Leigh syndrome
**
CF of Leigh Syndrome
1) Developmental delay
2) ) loss of bladder fxn
3) ) Dystonia,
4) ataxia,
5) loss of speach,
6) Dysphagia
7) Eventually , Central respiraotry failure
Leigh Syndrome genetics?
can be:
1) Mitochondrial inheritance
2) AR
3) XL
GENETICS
Leigh Syndrome –> 10-20% are Mitochondrial inheritance, where there ———– mutation in ———-
Leigh Syndrome –> 10-20% are Mitochondrial inheritance, where there T8993G/C mutation in MT-ATP6
AR cases of Leigh Syndrome are caused by mutations in ———
SURF1/SDHA/Complex I subunit & assembly factor genes
XL cases of Leigh Sydrome are caused by mutations in ——-
PDHA1
Multifactoral disorders [Follow/ do not follow] a Mendelian pattern of inheritance
Do not
Examples of Multifactorial disorders
1) Epilepsy
2) Diabetes mellitus type 1
3) Cleft lip and palate
4) Ischaemic heart disease
Only small minority of Ischaemic heart disease cases are linked to Mendelian disorders, these are caused by mutations in?
LDLR
Monogenic form of DM type 1
MODY (1-2% dibaetes)
note:
monogenic -> involving/ controlled by a single gene
Monogenic mutations of Type 1 Diabetes
- HNF1A (30-50%),
- GCK ( 30-50%),
- HNF4A (5%)…
MOI of non-Syndromic Cleft lip and palate
Multifactorial inheritance
Non-Syndromic CL&P are caused by mutations in?
No single major locus
- some genes MSX1, IRF6
Multifactorial disorders Have a Complex pattern of inheritance such as:
- Multiple ———–
- ———- Influences
- Multiple Genetic varients
- Eviromental influences
Enviromental factors that cause Non-Syndromic Cleft lip and palate
1) anti-epileptic drugs
2) Impaired folic acid metabolism
3) Smoking
In multifactorial inheritance there is NO ———- or ——– of genes (equal additive effect)
No dominance or recessivenessof these genes (equal additive effect)
In multifactorial inheritance ———– interacts with the genotype to produce the final phenotype
Enviroment
MOI of Epilepsy
Multifactorial inheritance
cause (Etiology) of Epilepsy
1) Idiopathic
2) genetic (formerly idiopathic)
3) Structural/ metabolic (sympotmatic) –> HIE, trauma, tumour, infection, stroke
* HIE: Hypoxic-Ischemic Encephalopathy
Common genetic cause of Epilepsy
- Common variants (GWAS) – few identified - ILAE consortium
- Rare variants – some identified (CNVs, ion channels, others) - Epi4K/25K
how does genetic variation cause Epilepsy
1) Mendelian variation (Characteristics controlled by a single gene) or
2) Polygenic variation (influenced by many genes)
Monogeneic vs Polygenic Gene variation
MOI in Marfan syndrome
AD , loss of function
(Haploinsufficiency mutations)
**
Type of mutation in Marfan Syndrome
FBN1 on chromosome 15q21- fibrillin gene
* Loss-of-fx, AD
loss of function of mutations in AD inheritance are based on ?
Hapoloinsufficiency
(when one copy of the gene is inactivated/deleted and the remaining functional copy of the gene is inadequent- non functional e.g. FBN1 in Marfan)
———: Encoded proteins that in their normal state, negatively regulate proliferation (e.g, Prevent tumour growth)
Tumour supresser genes (loss of function mutations)
——— drive tumour growth
Oncogene
will loss of function of TSGs (Tumour supressor genes) cause cancer?
If only one allele (not both) is affected then one TSG is enough to sustain tumour supression
- Note:
Second allele must malfunction for tumour to develop
At the tissue level, oncogenesis acts [recessively /dominantly] BUT the tumour predisposition syndrome is inherited as a [dominant/recessive] trait
At the tissue level, oncogenesis acts recessively BUT the tumour predisposition syndrome is inherited as a dominant trait
loss of mutation in Tumour supressor genes are inherited ———–
dominantly
- however expressed recessively at tissue level (both alleles must be “mutated” for the TSG to be non functional
Examples of AD- Gain of Function mutations
1) Charchot-Marie-Tooth - PMP22 duplication
2) FGFR3 mutation in Achondroplasia
3) CAG repeat in HD
Dominant negative mutations are comnon in genes coding structural proteins that are ———- and —–
Dominant negative mutations are comnon in genes coding structural proteins that are dimers and multimers
———— Mutant gene product results in the loss of protein activity/ function by interfering with the normal gene product of the corresponding allele
Dominant Negative mutations
Examples of Dominant negative mutations
COL1A1/2 in
osteogenesis Imperfecta (OI)
————- mutations in the COL1A1 gene in OI –> results in MILD disease
Loss-of-function mutations in the COL1A1 gene
———- mutations in the COL1A1 gene in OI –> Severe disease
Missense mutations in the COL1A1 gene
* has a dominant negative effect
MOI?
MOI?
