MITOCHONDRIAL INHERITANCE

•  Some of the estimated 20,000 genes in the human genome are located in small compartments in the cell called the mitochondria, rather than on chromosomes in the cell’s nucleus. Some cells contain many hundreds of mitochondria.


• The genes found within the mitochondria contain the information that codes for the production of many of the important enzymes that drive the biochemical reactions to produce the body’s source of energy. The cells in the body, especially in organs such as the brain, heart, muscle, kidneys and liver, cannot function normally unless they are receiving a constant supply of energy.


• Faulty mitochondrial genes can result in absence of these enzymes, or enzymes that are impaired and do not work properly.
This leads to a reduction in the supply of ATP, and may result in problems with the body’s functions

• The pattern of inheritance of conditions due to faulty mitochondrial genes is often called maternal inheritance. This is because
a child inherits the great majority of their mitochondria from their mother through the egg.

• Usually a mother will have a mixture of mitochondria containing the working gene copy and others containing the faulty gene.
For a condition to develop, the number of mitochondria with the faulty gene must be above a critical level (the threshold)

• The cells of different tissues and organs can have varying amounts of mitochondria with a faulty gene, and the number of cells
with the faulty mitochondria in each tissue or organ may vary

• Conditions due to having faulty mitochondrial genes create complexities when assessing the risk the mother has for passing on
the faulty mitochondrial genes to a child and if, or how severely, the child would be affected
• While it is possible to test for the presence or absence of some faulty mitochondrial genes and their products during pregnancy,
the result may be difficult to interpret
• Whether symptoms of the condition will occur or not depends on whether the numbers of mitochondria with the faulty genes
is above the critical threshold in enough cells to interfere with energy production
• Genetic counselling can provide the most current information on the availability and appropriateness of testing for mitochondrial conditions, either in an affected person or during pregnancy.


MNEMONIC- MITOCHONDRIAL DISORDERS :


KLMNOP


K-     KSS


L-     LHON
         Leigh's disease


M-    Mitochondrial myopathy
         Mitochondrial deletion
         MELAS
         MERRF
         MMC


N-    NARP
        Navajo neurohepatopathy.


O-    Chronic Progressive External Opthalmoplegia


P-     Pearson Syndrome

Linkage and Association Studies

There are two primary strategies for mapping genes that cause or increase susceptibility to human disease:
(1) classic linkage can be performed based on a known genetic model or, when the model is unknown, by studying pairs of affected relatives.
(2) disease genes can be mapped using allelic association studies.

Genetic Linkage


Genetic linkage refers to the fact that genes are physically connected, or linked, to one another along the chromosomes.

Two fundamental principles are essential for understanding the concept of linkage:

(1) when two genes are close together on a chromosome, they are usually transmitted together, unless a recombination event separates them.
(2) the odds of a crossover, or recombination event, between two linked genes is proportional to the distance that separates them. Thus, genes that are further apart are more likely to undergo a recombination event than genes that are very close together.

The detection of chromosomal loci that segregate with a disease by linkage can be used to identify the gene responsible for the disease (positional cloning) and to predict the odds of disease gene transmission in genetic counseling.

Polymorphisms are essential for linkage studies because they provide a means to distinguish the maternal and paternal chromosomes in an individual. On average, 1 out of every 1000 bp varies from one person to the next. Although this degree of variation seems low (99.9% identical), it means that >3 million sequence differences exist between any two unrelated individuals and the probability that the sequence at such loci will differ on the two homologous chromosomes is high (often >70–90%). These sequence variations include VNTRs, short tandem repeats (STRs), and SNPs. Most STRs, also called polymorphic microsatellite markers, consist of di-, tri-, or tetranucleotide repeats that can be measured readily using PCR. Characterization of SNPs, using DNA chips, provides an important new tool for comprehensive analyses of genetic variation, linkage, and association studies. Although these sequence variations usually have no apparent functional consequences, they provide much of the basis for variation in genetic traits.

In order to identify a chromosomal locus that segregates with a disease, it is necessary to characterize polymorphic DNA markers from affected and unaffected individuals of one or several pedigrees. One can then assess whether certain marker alleles cosegregate with the disease.

Markers that are closest to the disease gene are less likely to undergo recombination events and therefore receive a higher linkage score.
Linkage is expressed as a lod (logarithm of odds) score—the ratio of the probability that the disease and marker loci are linked rather than unlinked. Lod scores of +3 (1000:1) are generally accepted as supporting linkage, whereas a score of –2 is consistent with the absence of linkage.


Allelic association refers to a situation in which the frequency of an allele is significantly increased or decreased in individuals affected by a particular disease in comparison to controls.

Linkage and association differ in several aspects. Genetic linkage is demonstrable in families or sibships. Association studies, on the other hand, compare a population of affected individuals with a control population. Association studies can be performed as case-control studies that include unrelated affected individuals and matched controls, or as family-based studies that compare the frequencies of alleles transmitted or not transmitted to affected children. Allelic association studies are particularly useful for identifying susceptibility genes in complex diseases.

When alleles at two loci occur more frequently in combination than would be predicted (based on known allele frequencies and recombination fractions), they are said to be in linkage disequilibrium .

Nucleotide Repeat Expansion Disorders

Several diseases are associated with an increase in the number of nucleotide repeats above a certain threshold . The repeats are sometimes located within the coding region of the genes, as in Huntington disease or the X-linked form of spinal and bulbar muscular atrophy (SBMA, Kennedy syndrome). In other instances, the repeats probably alter gene regulatory sequences.

If an expansion is present, the DNA fragment is unstable and tends to expand further during cell division. The length of the nucleotide repeat often correlates with the severity of the disease. When repeat length increases from one generation to the next, disease manifestations may worsen or be observed at an earlier age; this phenomenon is referred to as anticipation. In Huntington disease, for example, there is a correlation between age of onset and length of the triplet codon expansion. Anticipation has also been documented in other diseases caused by dynamic mutations in trinucleotide repeats . The repeat number may also vary in a tissue-specific manner. In myotonic dystrophy, the CTG repeat may be tenfold greater in muscle tissue than in lymphocytes .

Selected Trinucleotide Repeat Disorders

X-chromosomal spinobulbar muscular atrophy (SBMA)
Xq11-q12
CAG
XR
Androgen receptor

Fragile X-syndrome (FRAXA)         Fragile X-syndrome (FRAXE)
CGG                                                GCC
XR                                                   XR
FMR-1 protein                                 FMR-2 protein


Dystrophia myotonica (DM)
CTG
AD, variable penetrance
Myotonin protein kinase

Huntington disease (HD)
CAG
AD
Huntingtin

Spinocerebellar ataxia type 1 (SCA1)
CAG
AD
Ataxin 1

Spinocerebellar ataxia type 2 (SCA2)
CAG
AD
Ataxin 2

Spinocerebellar ataxia type 3 (SCA3); Machado Joseph disease (MD)
CAG
AD
Ataxin 3

Spinocerebellar ataxia type 6 (SCA6, CACNAIA)
CAG
AD
Alpha 1A voltage-dependent L-type calcium channel

Spinocerebellar ataxia type 7 (SCA7)
CAG
AD
Ataxin 7

Spinocerebellar ataxia type 12 (SCA12)
CAG
AD
Protein phosphatase 2A

Dentorubral pallidoluysiane atrophy (DRPLA)
CAG
AD
Atrophin 1

Friedreich ataxia (FRDA1)
GAA
AR
Frataxin

X-inactivation, Imprinting, and Uniparental Disomy

According to traditional Mendelian principles, the parental origin of a mutant gene is irrelevant for the expression of the phenotype. There are, however, important exceptions to this rule.

 X-inactivation prevents the expression of most genes on one of the two X-chromosomes in every cell of a female.
Gene inactivation also occurs on selected chromosomal regions of autosomes. This phenomenon, referred to as genomic imprinting, leads to inheritable preferential expression of one of the parental alleles. It is of pathophysiologic importance in disorders where the transmission of disease is dependent on the sex of the transmitting parent and, thus, plays an important role in the expression of certain genetic disorders. Two classic examples are the Prader-Willi syndrome and Angelman syndrome .

Prader-Willi syndrome is characterized by diminished fetal activity, obesity, hypotonia, mental retardation, short stature, and hypogonadotropic hypogonadism. Deletions of the paternal copy of the Prader-Willi locus located on the short arm of chromosome 15 result in a contiguous gene syndrome involving missing paternal copies of the necdin and SNRPN genes, among others. In contrast, patients with Angelman syndrome, characterized by mental retardation, seizures, ataxia, and hypotonia, have deletions involving the maternal copy of this region on chromosome 15. These two syndromes may also result from uniparental disomy. In this case, the syndromes are not caused by deletions on chromosome 15 but by the inheritance of either two maternal chromosomes (Prader-Willi syndrome) or two paternal chromosomes (Angelman syndrome).

Genomic imprinting, or uniparental disomy, is involved in the pathogenesis of several other disorders and malignancies. For example, hydatidiform moles contain a normal number of diploid chromosomes, but they are all of paternal origin. The opposite situation occurs in ovarian teratomata, with 46 chromosomes of maternal origin.

Expression of the imprinted gene for insulin-like growth factor II (IGF-II) is involved in the pathogenesis of the cancer-predisposing Beckwith-Wiedemann syndrome (BWS). These children show somatic overgrowth with organomegalies and hemihypertrophy, and they have an increased risk of embryonal malignancies such as Wilm's tumor. Normally, only the paternally derived copy of the IGF-II gene is active and the maternal copy is inactive. Imprinting of the IGF-II gene is regulated by H19, which encodes an RNA transcript that is not translated into protein. Disruption or lack of H19 methylation leads to a relaxation of IGF-II imprinting and expression of both alleles.

Meiotically and mitotically heritable changes in gene expression not associated with DNA sequence alterations are referred to as epigenetic effects. These changes involve DNA methylation, histone modifications, and RNA-mediated silencing, resulting in gene repression without a change in the coding sequence. Epigenetic alterations are increasingly recognized to play a role in human diseases such as cancer, mental retardation, hematologic disorders, and possibly in aging. For example, de novo methylation of CpG islands, regions of >500 bp in size with a GC content >55% in promoter regions that are normally unmethylated, is a hallmark of human cancers. Inhibitors of enzymes controlling epigenetic modifications such as histone deacetylases and DNA methyltransferases reverse gene silencing and represent a promising new group of antineoplastic agents.

Mosaicism

Mosaicism refers to the presence of two or more genetically distinct cell lines in the tissues of an individual. It results from a mutation that occurs during embryonic, fetal, or extrauterine development.

The developmental stage at which the mutation arises will determine whether germ cells and/or somatic cells are involved.

Chromosomal mosaicism results from non-disjunction at an early embryonic mitotic division, leading to the persistence of more than one cell line, as exemplified by some patients with Turner syndrome .

Somatic mosaicism is characterized by a patchy distribution of genetically altered somatic cells. The McCune-Albright syndrome, for example, is caused by activating mutations in the stimulatory G protein (Gs-alpha) that occur early in development . The clinical phenotype varies depending on the tissue distribution of the mutation; manifestations include ovarian cysts that secrete sex steroids and cause precocious puberty, polyostotic fibrous dysplasia, café-au-lait skin pigmentation, growth hormone–secreting pituitary adenomas, and hypersecreting autonomous thyroid nodules.

Mitochondrial Disorders

Mendelian inheritance refers to the transmission of genes encoded by DNA contained in the nuclear chromosomes. In addition, each mitochondrion contains several copies of a small circular chromosome. The mitochondrial DNA (mtDNA) is ~16.5 kb and encodes transfer and ribosomal RNAs and 13 proteins that are components of the respiratory chain involved in oxidative phosphorylation and ATP generation.

The mitochondrial genome does not recombine and is inherited through the maternal line because sperm does not contribute significant cytoplasmic components to the zygote. A noncoding region of the mitochondrial chromosome, referred to as D-loop, is highly polymorphic. This property, together with the absence of mtDNA recombination, makes it a valuable tool for studies tracing human migration and evolution, and it is also used for specific forensic applications.

Inherited mitochondrial disorders are transmitted in a matrilineal fashion; all children from an affected mother will inherit the disease, but it will not be transmitted from an affected father to his children . Alterations in the mtDNA affecting enzymes required for oxidative phosphorylation lead to reduction of ATP supply, generation of free radicals, and induction of apoptosis.

 Several syndromic disorders arising from mutations in the mitochondrial genome are known in humans and they affect both protein-coding and tRNA genes . The broad clinical spectrum often involves (cardio)myopathies and encephalopathies because of the high dependence of these tissues on oxidative phosphorylation. The age of onset and the clinical course are highly variable because of the unusual mechanisms of mtDNA transmission, which replicates independently from nuclear DNA.

During cell replication, the proportion of wild-type and mutant mitochondria can drift among different cells and tissues. The resulting heterogeneity in the proportion of mitochondria with and without a mutation is referred to as heteroplasmia and underlies the phenotypic variability that is characteristic of mitochondrial diseases.

Selected Mitochondrial Diseases

1. MELAS syndrome: mitochondrial myopathy with encephalopathy, lactacidosis, and stroke

2. Leber's optic atrophy: hereditary optical neuropathy

3. Kearns-Sayre syndrome (KSS): ophthalmoplegia, pigmental degeneration of the retina, cardiomyopathy

4. MERRF syndrome: myoclonic epilepsy and ragged-red fibers

5. Neurogenic muscular weakness with ataxia and retinitis pigmentosa (NARP)

6. Progressive external ophthalmoplegia (CEOP)

7. Pearson syndrome (PEAR): bone marrow and pancreatic failure

8. Autosomal dominant inherited mitochondrial myopathy with mitochondrial deletion (ADMIMY)

9. Somatic mutations in cytochrome b gene: exercise intolerance, lactic acidosis, complex III deficiency, muscle pain, ragged-red fibers


Acquired somatic mutations in mitochondria are thought to be involved in several age-dependent degenerative disorders affecting predominantly muscle and the peripheral and central nervous system (e.g., Alzheimer's and Parkinson's disease). Establishing that a mtDNA alteration is causal for a clinical phenotype is challenging because of the high degree of polymorphism in mtDNA and the phenotypic variability characteristic of these disorders. Certain pharmacologic treatments may have an impact on mitochondria and/or their function. For example, treatment with the antiretroviral compound azidothymidine (AZT) causes an acquired mitochondrial myopathy through depletion of muscular mtDNA.