MUTATION IN MITOCHONDRIAL DNAAND HUMAN HEALTH

AMEENA THUSLEEN .NI MSc – Biomedical GeneticsDr. ALM P.G. IBMSUniversity of Madras

MITOCHONDRION

Mitochondrion is a double membrane bound cell organelle . It is present in all eukaryotic cells . It was first described by Richard Altmann in 1890 and he called them as ‘bioblast’ . It plays a main role in cellular respiration and energy production i.e ATP synthesis , thus it is called as ‘Power House’ of the cell . Unlike other cell organelle mitochondria has its own genome .

MITOCHONDRIAL GENOME• The mitochondrial genome is a circle, 16.6 kb of

double stranded DNA . • The two strands are notably different in base

composition, leading to one strand being “heavy” (the H strand) and the other light (the L strand).

• Both strands encode genes, although more are on the H strand.

• A short region, the D loop (D = “displacement”), is a DNA triple helix, there are 2 overlapping copies of the H strand.

• The D loop is also the site where most of replication and transcription is controlled.

• Human mitochondrial genes contain no introns .

MITOCHONDRIAL GENOME STRUCTURE

MITOCHONDRIAL GENES• Genes: total of 37 - 22 tRNAs , 2 rRNAs, 13

polypeptides. • tRNA: only 60 of the 64 codons code for amino

acids. 8 tRNAs cover all 4 3rd base positions with the same amino acid, and the remaining 14 tRNAs each cover 2 3rd base positions (purines or pyrimidines). Thus, all 60 codons are covered.

• rRNA: 16S and 23S which are standard sizes for bacterial rRNAs .

• polypeptides: all are components of the electron transport chain. Other components are encoded in the nucleus and transported to the mitochondria after translation.

COMPARISON BETWEEN THE HUMAN NECLEAR DNA AND MITOCHONDRIAL DNA

Characteristic Nuclear genome Mitochondrial genome Size ~ 3.3 × 10 bp 16,569 bp

Number of DNA molecule per cell

23 in haploid cells; 46 in diploid cells

Several thousand copies per cell (polyploidy)

Number of genes encoded ~ 20,000 to 30,000 37

Gene density ~1 per 40,000 bp ~1 per 450 bp

Introns Frequently found in most genes

Absent

Percentage of coding DNA ~ 3 % ~ 93 %

Codon usage The universal genetic code AUA - methionine; TGA –tryptophan ; AGA & AGG specify stop codons

Mode of inheritance Mendelian inheritance for the autosomes and the X chromosomes

Exclusively maternal

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HOMOPLASMY AND HETEROPLASMY

HOMOPLASMY : Homoplasmy is a term used in genetics to

describe a eukaryotic cell whose copies of mtDNA are all identical .

HETEROPLASMY : Heteroplasmy is the presence of more

than one type of mtDNA which has a mixture of both wild type and mutant DNA in a single cell .

Heteroplasmy is a rare condition and is often associated with mitochondrial DNA disease .

Conti… The rate of heteroplasmy formation is a product of

random segregation between wild type and mutant DNA occurring during early embryogenesis .

MITOCHONDRIAL INHERITANCE• All mitochondrial DNA in the zygote , is

derived from the ovum. Therefore . A mother carrying a mtDNA will pass it on to all her children , but only her daughter will transmit it to their progeny .

• The paternal transmission of mitochondrial DNA was reported in skeletal muscle in a patient with a mitochondrial myopathy (Schawarts and Vissing , 2002) .

GENE MUTATION• A mutation is defined as an inherited change in genetic

information .• Mutations cause changes in the genetic code that lead to genetic

variations and the potential to develop disease. Gene mutations can be classified in two major ways ,• Hereditary mutations are inherited from a parent .These

mutations are also called germline mutations because they are present in the parent’s egg or sperm cells (germ cells)

• Acquired (or somatic) mutations occur at some time during a person’s life and are present only in certain cells. These changes can be caused by environmental factors such as ultraviolet radiation or can occur if a mistake is made as DNA copies itself during cell division. Acquired mutations in somatic cells cannot be passed on to the next generation.

TYPES OF GENE MUTATIONS• Base substitution mutation : The alternation

of a single nucleotide in the DNA . Base substitutions are of two types. I ) Transition: In a transition, a purine is

replaced by a different purine or, alternatively, a pyrimidine is replaced by a different pyrimidine .

II) Transversion : In a transversion, a purine is replaced by a pyrimidine or a pyrimidine is replaced by a purine.

• Insertion and deletion mutation : The addition or the removal , of one or more

nucleotide pairs . Insertions and deletions within sequences that

encode proteins may lead to frameshift mutations, changes in the reading frame of the gene.

MITOCHONDRIAL MUTATION RATE• The rate of mutation in mtDNA is 10 to 17

times higher than nuclear gene .• Several possible factor that may cause the

high mutation rate in mtDNA include ,• Insufficient DNA repair system• Lack of DNA proteins such as histones• Spontaneous error arising during DNA

replication etc

HUMAN MITOCHONDRIAL DISORDERS

Mitochondrial disorders are clinically heterogenous group of disorders that arise as a result of dysfunction of mitochondrial respiratory chain .

There are more than 500 point mutations and 200 deletions and rearrangements in mtDNA have been associated with various diseases.

The clinical syndromes associated with mtDNA mutations are extremely variable and patients can present at any stage in life .

HEARING LOSS• Inherited hearing loss can be due to both

heteroplasmic and homoplasmic mitochondrial mutation .

I) Mitochondrial syndromic hearing loss :• The neuromuscular syndroms such as KSS ,

MELAS which are frequently associated with hearing loss as one of their signs .

• All mitochondrial mutations leading to hearing loss are in tRNA genes .

II) Mitochondrial Nonsyndromic hearing loss :• Several mtDNA mutations leading to

nonsyndromic hearing loss have been reported .

• Unlike syndromic hearing loss , non syndromic hearing loss associated with homoplasmic condition .

Leigh syndrome : 20 to 25 percent of Leigh syndrome cases are caused by

mutations in mitochondrial DNA . Leigh syndrome is a progressive neurodegenerative condition, which particularly affects the brainstem,

diencephalon, and basal ganglia. Leigh syndrome is due to severe failure of oxidative metabolism . symptoms :• diarrhea, vomiting , and dysphagia (trouble swallowing or

sucking)• Excess lactate may be deposited in the urine, cerebrospinal

fluid, and blood in a condition called lactic acidosis.• hypotonia (low muscle tone and strength)• Dystonia (involuntary, sustained muscle contraction) etc

Leigh syndrome

Kearns–Sayre syndrome (KSS):• KSS is associated with the development of retinitis

pigmentosa and progressive external ophthalmoplegia occurring before the age of twenty

Symptoms : paralysis of certain eye muscles (which gets worst over

timedegeneration of the retina (only the part that has to do

with sight) over time you may receive other symptoms, such as

muscle weakness, difficulty walking or moving, brain damage, deafness, and heart disease

Kearns–Sayre syndrome (KSS):

Pearson syndrome: • This is a rare disorder of infancy• characterised by sideroblastic anaemia

(abnormal nucleated erythroblast )with pancytopaenia(reduction in the number of RBC and WBC, as well as Platelets) and exocrine pancreatic failure.

• The clinical course in these children can be severe leading to early death. In those that survive the blood disorder improves but they later develop the clinical features of KSS.

• In these children, there is a very high level of large-scale single mtDNA deletion present in all tissues .

Pearson syndrome

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS):

MELAS is a progressive neurodegenerative disorder with typical onset between the ages of 2 and 15 .

It is the most common inherited mitochondrial disease . Clinical Features: Strokes, myopathy, muscle twitching,

dementia (memory loss), and deafness . Symptoms: vomiting, migraine(severe) like headaches,

diabetes, droopy eyelids, muscle weakness, and short stature . gradual cumulative effects of these episodes often result in

variable combinations of loss of motor skills (speech, movement, and eating), impaired sensation (vision loss and loss of body sensations), and mental impairment (dementia).

Conti…. The disease occurs with the first stroke-like

episode (usually 14-15 years of age) Mutations in MT-TL1 cause more than 80

percent of all cases of MELAS. They impair the ability of mitochondria to make proteins, use oxygen, and produce energy.

This is a progressive disorder with a high mortality rate.

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS):

Chronic progressive external ophthalmoplegia (CPEO)

• One of the most common presentations of mtDNA disease in adults is CPEO.

• CPEO is characterised by a progressive paralysis of the eye muscles .

• leading to impaired eye movement and ptosis (drooping or falling of the upper eyelid )

• CPEO is typically caused by sporadic large-scale single deletions or multiple mtDNA deletions

• In patients with CPEO, there may be other features depending on the underlying genetic defect but myopathy and fatigue are common in all patients.

Chronic progressive external ophthalmoplegia (CPEO)

REFERENCES :• Pierce Benjamin A. (2013) Genetics An

conceptual Approach Fourth ed. W. H. Freeman and Company., ISBN-13: 978-1-4292-3250-0

• Thesis on Study of Mitochondrial Mutations Causing Nonsyndromic Hearing Loss in South Indian Hearing Impaired ,by M. SUBATHRA , Dept of Genetics , Dr.ALM PG IBMS , July 2012.

• http://biology.tutorvista.com/animal-and-plant-cells/mitochondria.html

• http://www.nature.com/gt/journal/v15/n14/full/gt200891a.html

• http://www.mitoresearch.org/mitodiseases2.html

• http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/genemutation

• https://www.rarediseasesnetwork.org/NAMDC/learnmore/diseases.htm

• http://www.sciencedirect.com/science/article/pii/S0005272809002618

• http://www.sciencedirect.com/science/article/pii/S0005272809002618

• http://ghr.nlm.nih.gov/