You sequence the BMPR2 gene in all. of your PAH patients and identify the follow

Question

You sequence the BMPR2 gene in all. of your PAH patients and identify the following 4 mutation carriers. For each individual, list (U) the consequence of the mutation on the BMPR2 protein and (ii) whether or not they should be included in your Ataluren trial. (8 mark) Patient #1 Patient #3 Wild type sequence: CGGICCCIGG CGG Wild type sequence: TTACCCICAT CGG Mutant sequence: TTACCC CATCGA Mutant sequence: CGGICCCTGA Exon#: [1121314131-6 171819110111 Exon #: |1| 2 | 3 |4|5| 6 | 7| 8 |9|10|11 12 13 Patient #2 Patient #4 Wild type sequence: TTTTGT CACIGTT Mutant sequence: TTTTGG CAC Wild type sequence: TCTICCT ACTITCC Mutant sequence: TCO CTA CTT

Explanation / Answer

(i)

In the original sequence, the codon TGG codes for a mRNA codon of UGG. This codes for the amino acid tryptophan. But, in the mutant sequence of the patient 1, TGA codes for the mRNA codon of UGA. This codon is a stop codon and stops the synthesis of the protein prematurely.

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In the original sequence, the codon CGG codes for the same mRNA codon. This codes for the amino acid Arginine. In the mutant sequence of the patient 3, CGA codes for the same mRNA codon. This codon also codes for arginine. Since both the original and the mutant codons code for the same amino acid, it is a silent mutation and will not harm the protein sequence in any way.

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In the original sequence, the codon TGT codes for the mRNA codon UGU. This codes for the amino acid cystiene. In the mutant sequence of patient 2, the codon TGG codes for the mRNA codon UGG. This codes for the amino acid tryptophan. Since this is a point mutation,the protein is slightly altered. Since the amino acid cystiene has a sulfur group which usually participates in bonding, the presence of tryptophan will affect the bonding at this site.

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In the original sequence, we see the amino acids - Ser- Pro- Thr - Ser. In the patient sequence 4,we see mutations in all the 4 codons. The mutant sequence gives the following sequence - Ser-Leu-Leu-Pro.

Here we see that only the first mutation is a silent mutation in which both the original and mutant codons code for the same amino acid. All the other three amino acids are changed. In place of proline which has a bulky side group, we see leucine which has a small side group. This will give a problem for the folding of the protein. In the last codon we see that the serine group has been replaced with proline which has a bulky side group. This will also cause a problem with the intraprotein interactions and folding of the protein.

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The first three mutations can be included in the trial since it is easy to correlate the symptoms with the mutation. In the fourth mutation, since all codons are mutated,we cannot correlate the symptoms of the patients with the specific mutation

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