Genetics 4 - Mitochondria Flashcards

Question

heteroplasmy

Answer 1

variation in mtDNA sequences (common)

Answer 2

variation between cells

Answer 3

variation within cells

Answer 4

mutation as mitochondria do not undergo recombination during cell division

Answer 5

proportion of mtDNA sequences in each cell/tissue that carries the dysfunctional allele may vary during cell division random segregation of mito. (and mtDNA) between 2 daughter cells occurs however mtDNA mutations in somatic cells are not heritable

Answer 6

phentoypically affected daughter cells are the ones that end up with more mito. with mutated DNA Incomplete penetrance Variable expressivity Pliotrophy - 1 gene can influence 2 or more seemingly unrelated phenotypic traits

Answer 7

1 gene can influence 2 or more seemingly unrelated phenotypic traits

Answer 8

different oocytes from one woman may vary in the extent of heteroplasmy some may get a high proportion of pathogenic mtDNA - genetic bottleneck predicting phenotype from genotype and genetic counselling

Answer 9

proportion of pathogenic mtDNA in tissues of each family member highly variable

Answer 10

identical mtDNA mutations may be associated with different manifestations can also happen that very similar manifestations arise from different mutations

Answer 11

multi-organ degenerative disease especially high energy organ systems CNS muscle (skeletal and heart) liver kidney

Answer 12

bilateral, painless, subacute visual failure that develops during young adult life males are 4x more likely to be affected than females

Answer 13

entirely asymptomatic until onset in 1 eye similar symtpoms appear in other eye an average of 8 weeks later in 25% of cases, visual loss is bilateral at onset small % of cases, central vision gradually improves but recovery is incomplete for most central vision loss is profound and permanent some individuals with LHON, usually women, may also have MS like illness - LHON plus

Answer 14

point mutation

Answer 15

m.3460G\>A in MT-ND1

Answer 16

m.11778G\>A in MT-ND4

Answer 17

m.14484T\>C in MT-ND6 FOUNDER EFFECT = Small population that interbreed ⇒ Higher incidence of particular allele

Answer 18

(difference in mito. sequence in DNA =) heteroplasmy in polymorphonuclear leukocytes occurs in circa 10-15% of those with a pathogenic LHON causing mtDNA sequence individuals with a m.11778G\>A pathogenic variant load of \<75% in their leukocytes may be unaffected heteroplasmy in cone cells may influence risk of developing visual impairment in general heteroplasmy of \< 75% pathogenic variant load is rare majority of LHON carriers are homoplasmic

Answer 19

homoplasmic

Answer 20

avoid smoking limit alcohol use avoid other environmental toxins diet

Answer 21

gender and age dependent penetrance - 50 (av age of onset) mother of a proband usually has the mtDNA mutation and may or may not have symptoms up to 40% of cases = SIMPLEX - occur in a single individual in a family

Answer 22

a male (affected or unaffected) with a primary LHON-causing mtDAN mutation cannot transmit the mutation to any of his offspring a female (affected or unaffected) with a primary LHON-causing mtDNA mutation transmits the mutation to all of her offspring but to varying degrees (heteroplasmy) - Depends on proportion of mutated mtDNA that ends up in the ova that make the child - Also environmental factors - THRESHOLD EFFECT

Answer 23

mtDNA mutational load in amniocytes and chorionic villi is unlikely to correspond to that of other foetal or adult tissues presence of mtDNA mutation does not reliably predict the occurence, age of onset, severity, or rate of disease progression

Answer 24

50% of males, 10% of females who harbour a primary LHON causing mtDNA mutation become affected a compensatory mechanism of activated mitochondrial biogenesis and increased mtDNA copy number may explain why some carriers are unaffected promoted by oestrogens in females, which amy partially explain the gender bias

Answer 25

true affected person is more likely to homoplasmic than a non-affected person

Answer 26

males with mtDNA mutation 4x more likely to manifest LHON than females with the same mtDNA mutation

Answer 27

describes individual branches, or closely related groups of branches, on the genetic family tree of all humans all members of a haplogroup can trace their ancestry back to a single individual haplogroups arose through mutation and migration

Answer 28

mtDNA sequence polymorphism variations that have occurred over more than 150,000 years and correlate with the geographic origins of populations traced through maternal lineages

Answer 29

de novo mutation

Answer 30

by aligning mtDNA sequences members of a haplogroup have a MRCA subclades within haplogroups with an even MRCA

Answer 31

members of an mtDNA haplogroup have more similar total mtDNA to other members of the same haplogroup have similar mutations/polymorphisms in other mtDNA genes as most mtDNA codes for proteins, mito. polymorphisms can influence energy metabolism and contribute to the expression of the overall clinical phenotype

Answer 32

higher incidence among mtDNA haplogroups H but lower for J and K

Answer 33

H haplogroup

Answer 34

Y chromosome EXCEPT FOR pseudoautosomal region

Answer 35

the central dogma of maternal inheritance of mtDNA remains valid there are some exceptional cases where paternal mtDNA could be passed to the offspring

Answer 36

progressive neurometabolic disorder 50% mortality per year from diagnosis

Answer 37

mito. dysfunction caused by hereditary genetic defect MRI necrotising lesions in the midbrain and brainstem bilateral symmetrical degeneration of the brainstem, cerebellum and basal ganglia typical onset in infancy or childhood, often after a viral infection (metabolic challenge) may begin later 1 in 40,000 births

Answer 38

elevated lactic acid (blood and CSF) bilateral lesions in the thalami, posterior parietal and temporal lobes positive on metabolic screening cough, cold, fever, difficulty breathing seizures slow to obtain developmental milestones dysarthria dysphagia hypertonic and involuntary movements palpable liver of 2cm below costal margin

Answer 39

criteria for LS only partially met despite overall clinical picture indicative of LS often peripheral nervous system involvement, including polyneuropathy or myopathy often non-neurological abnormalities - dysmorphic features, cardiac, endocrine and GI resp impairment due to brainstem involvement usually absent

Answer 40

mutations in at least 75 genes mito. disorder with broadest genetic (and clinical) heterogeneity pyruvate dehydrogenase (PDHC) deficiency (citric acid cycle) resp chain enzyme defects - complexes I, II, IV and V (ox phos) NARP mutation MERRF mutation

Answer 41

matrilineal (mitochondrial) 20% de novo mutation X linked recessive autosomal recessive so many patterns because so many genes are involved present in mtDNA, nuclear DNA, X chromosomes

Answer 42

on nuclear genome synthesised in cytoplasm and transported to mitochondria most inherited disorders of mito. are related to changes in nuclear DNA rather than mtDNA these mutations are inherited according to the classic Mendelian rules, not mitochondrial (matrilineal) inheritance

Answer 43

in the X linked pyruvate dehydrogenase (E1) and α subunit (PDHA1) [nuclear DNA] inheritance pedigree may appear autosoma lrecessive because parents are not usually affected in females (XX), a mutation would have to occur in both copies ofthe gene to cause the disorder unlikely, so males are affected by X linked recessive disorders much more frequently than females

Answer 44

mito. transplantation/donation can be done before or after fertilisation 3 parent embryo