When They Mutate by Dr. Apurva Mishra & Prof. R. K. Pandey - HTML preview

CLASSIFICATION OF GENETIC DISORDERS:

1. Chromosomal Disorders

2. Monogenetic conditions (Single gene disorder)

3. Polygenetic conditions (Multifactorial disorder)

4. Disorder with non-traditional mechanism of expression and inheritance

1. Chromosomal disorders:

These can be due to abnormality in number or structure of genes such as:

• Duplication
• Deletion
• Rearrangement
• Extra chromosomes

Rearrangement of chromosomal disorders can be further divided into:

• Balanced rearrangement – an altered state but doesn’t causes diseases
• Unbalanced rearrangement – an altered state causing diseases

2. Monogenetic conditions:

These follow Mendelian law of inheritance. Monogenetic conditions can be divided into four mode of inheritance:

• Autosomal Dominant: Autosomal dominant conditions accounts for presence of only one copy of altered allele at a locus. These are the most common genetic disorders reported in human beings. Individually it’s rare to find each autosomal dominant disorder, thus most affected child are as a result of mating between affected and unaffected parents(de-novo mutation). E.g. Huntingtons disease, Neurofibromatosis 1

FIG 1: A pedigree illustrating an autosomal dominant disorder. Affected individuals are depicted by colour. By convention, males are represented by square and females by circle.

• Autosomal Recessive: Autosomal recessive conditions accounts for presence of two copies of an altered allele at a locus to exhibit the dieases. Two unaffected people who each carry one copy of the mutated gene have a 25% chance with each pregnancy of having a child affected by the disorder. E.g. Cystic fibrosis, Sickle cell anemia, Spinal muscular atrophy.

FIG 2: A pedigree illustrating an autosomal recessive disorder. Affected individuals are depicted by solid colour and heterozygotes by partial shading.

• X- Linked Dominant: X-linked dominant disorders are caused by mutations in genes on the X chromosome. Only a few disorders have this inheritance pattern. Males are more frequently affected than females, and the chance of passing on  an X-linked dominant disorder differs between men and women. The male progeny of a man with an X-linked dominant disorder will not be affected, while his female progeny will inherit the condition. A woman with an X-linked dominant disorder has a 50% chance of having an affected daughter or son with each pregnancy. E.g Hypophosphatemia.
• X- Linked Recessive: X-linked recessive disorders are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females, and the chance of passing on the disorder differs between men and women. The  sons of a man with an X-linked recessive disorder will not be affected, and his daughters will carry one copy of the mutated  gene. With each pregnancy, a woman who carries an X-linked recessive disorder has a 50% chance of having sons who are affected and a 50% chance of having daughters who carry one copy of the mutated gene. E.g Hemophilia A, Duchenne muscular dystrophy, Color blindness.

FIG:3 A pedigree illustrating an X linked recessive disorder. Affected individuals are depicted by solid colour and heterozygous carrier by dots.

3. Polygenetic Conditions:

These are multifactorial disorders, determined by nongenetic or environmental factors. Polygenetic conditions do not follow Mendelian law of inheritance.

4. Non-traditional Mechanism of Expression & Inheritance:

Non-traditional mechanism of expression and inheritance occurs due to mutation in mitochondrial genome. It can be due to uniparental disomy i.e. two alleles from same locus inherited from one parent instead from both the parents. Hence it is also known as parent-of-origin effect.

MITOCHONDRIAL INHERITANCE:

Majority of genes are enclosed inside the nuclear genome, however there are small number of gene located on mitochondrial DNA (mt DNA). The mtDNA consist of 16.kb of circular DNA and accounts for 1% of total DNA. It encodes protein for aerobic respiration. Each cell having functional mtDNA will be identical (homoplasmy). However mutation in mtDNA will lead to a mix blend of expression (heteroplasmy). The proportion of mitochondrial mutated DNA will determine the phenotypic expression of mutation. More than 85% of mtDNA mutation before there is a phonotypical significant defect in aerobic respiratory chain.

To diagnose the disorders due to mutation in mtDNA muscle biopsy is profound over blood sampling to rule out false report, as in mtDNA mutation disorder there may be variation among different body tissues.

MUTATION: Mutation can be defined as alternation or change in genomic material. Mutation can be of two types depending upon the cell line involved:

• Somatic
• Germinal

At molecular level structural mutation can be majorly  divided into following types:

1. Single base pair substitution: It involves substitution of one  base pair for anther. Single base pair mutation is also known as point mutation. They can further be divided into :

• Missense mutation: Replacement of one amino acid for another. E.g. in Sickle cell anaemia disorder A to T substitution in sixth codon of globin gene.
• Non sense mutation: Replacement of an amino acid with stop codon i.e. UAA, UGA, UGA.
• Splice site mutation: A single base substitution which creates or destroys an intron-exon splice site.

2. Deletion: These may vary in size from single base pair to mega base pair. E.g. More than 60% of mutations in Duchenne muscular dystrophy are due to deletion in dystrophic gene.

3. Insertion & Duplication: They occur as result of unequal crossing over at meiosis.

4. Frameshift mutation: They can occur either due to deletion or single base pair substitution resulting in misreading of subsequent following codon.

5. Dynamic mutation: These occur when triplet of nucleotide repeated in a gene and the transmission of exact number of repeat is unstable and may increase in further generation. E.g. Fragile X syndrome, Mental retardation.

6. Inversion: It occurs when there is break in two chromosomes, the segments flip over and re-join, resulting in in correct translation.