Types of Gene mutations

A.  Single base pair change (Point Mutation)

B.  Deletions & Insertions

C.  Expansions of repeat sequences

A. Point mutation (Single base pair change)

  - is the substitution of one base for another.

  - includes the following types:-

1. Silent mutations

2. Missense mutations

3. Nonsense mutations

1. Silent (Synonymous) mutation. 

The genetic code is redundant (i.e. there is more than one codon for most amino acids) & therefore a change in one base may result in no change in the amino acid sequence of the protein. The base replacement does not lead to a change in the amino acid but only to the substitution of a different codon for the same amino acid. For example, the change of the codon UUU which codes for phenylalanine to UUC (i.e. the replacement of U by C) is a silent mutation because the new codon (UUC) also codes the same amino acid (phenylalanine).

2. Missense mutations

-  changes the codon for one amino acid to the codon for another amino acid.

-  is exemplified by the mutation which causes sickle cell anemia. 

 Hemoglobin is composed of a heme, two  α-globin polypeptide chains, & two  β-globin polypeptide chains. In normal individuals, the codon GAG codes for glutamic acid in the 6^th  position of the β-globin polypeptide chain. But in sickle cell anemia this codon is changed to GUG which codes valine.  Hence, as a result of this single base substitution, valine substitutes glutamic acid in the  β-globin chain. This amino acid substitution alters the physicochemical properties of hemoglobin, which is now called Hemoglobin S. This leads to sickle cell anemia. 

3. Nonsense mutation

-  changes the codon for an amino acid to a stop codon, leading to termination of translation of the mRNA transcript & a truncated protein. -  is exemplified by the mutation which causes β^o – thalassemia. In this, a substitution of U for C in the codon 39 of the  β globin chain of hemoglobin (i.e. the change of CAG to UAG) converts the codon for glutamine to a stop codon. This results in premature termination of the β globin gene translation. I.e. protein synthesis stops at the 38^th amino acid. This results in short peptide which is rapidly degraded leading to the absence of β-globin chains. This leads to β^o – thalassemia.

B. Deletions & insertions

- can occur within coding sequences or within noncoding sequences.

i. Deletions & insertions of one or two bases within coding sequences  lead to frameshift mutations because they alter the reading frame of the triplet genetic code in the mRNA so that every codon distal to the mutation in the same gene is read in the wrong frame.  This leads to altered amino acid sequence & usually premature termination of the peptide chain because of the occurrence of a termination codon in the altered reading frame.

ii. Deletion or insertion of three or a multiple of three base pairs within coding sequences  does not cause frameshift mutation, instead it results in abnormal protein missing one or more amino acid.

iii. Deletions affecting the promoter/enhancer sequences (i.e. in the noncoding regions) leads to promoter / enhancer mutations.

 C. Expansion of repeat sequences (trinucleotide repeat mutations)

-  show expansion of a sequence of 3 nucleotides. Normally, 3 nucleotides are repeated 20-30 times. Trinucleotide repeat mutation is when there is expansion of these normally repeated sequences  to more than 100 repeats.

-  The mechanism leading to an increase in the number of repeats is not clear. It is also not clear how the increase leads to disease.

-  cause myotonic dystrophy, Huntington’s disease, fragile X syndrome, etc…are not stable (i.e. they are dynamic) (i.e. the degree of amplification increases during gametogenesis).

This leads to the phenomenon of anticipation (i.e. the disease worsens during the subsequent generations).

References

Bezabeh ,M. ; Tesfaye,A.; Ergicho, B.; Erke, M.; Mengistu, S. and Bedane,A.; Desta, A.(2004). General Pathology. Jimma University, Gondar University Haramaya University, Dedub University.

مواضيع ذات صلة

داء ويلسون Wilson disease

متلازمة مارفان Marfan syndrome

مرض شاركوت - ماري- توث (Charcot-Marie-Tooth type 1A)

مرض ويلسون Wilsons disease

الثلاسيميا Thalassemia (أنيميا البحر المتوسط)

مرض الفينيل كيتون يوريا PKU) Phenylketonuria)

مرض تاي ساكس (Tay-sachs)

مرض فقر الدم المنجلي Sickle cell anemia

التليف الكيسي Cystic fibrosis

Cystic fibrosis

أهم الفحوصات التي تجرى لتشخيص الأمراض الوراثية

الثلاسيميا Thalassemia