WBR0099: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
No edit summary
No edit summary
Line 21: Line 21:
|MainCategory=Genetics
|MainCategory=Genetics
|SubCategory=Musculoskeletal/Rheumatology
|SubCategory=Musculoskeletal/Rheumatology
|Prompt=A 10-year-old boy is brought to the pediatrician's office by his mother for chronic weakness. She reports that her child started to have trouble rising from chairs at the age of six.  He has become progressively weaker over the past four years and now requires braces to walk. Physical examination is remarkable for proximal weakness of the upper and lower extremities. The pediatrician also notes atrophy of the gluteus maximus and accessory muscles of the pelvis, and unusually large calf muscles. The physician suspects a genetic disease and refers the patient to genetic testing.  Which of the following mutations is most likely present in this patient?
|Prompt=A 10-year-old boy is brought to the pediatrician's office by his mother for chronic weakness. She reports that her child started to have trouble rising from chairs at the age of six.  He has become progressively weaker over the past four years and now requires braces to walk. Physical examination is remarkable for proximal weakness of the upper and lower extremities. The pediatrician also notes atrophy of the gluteus maximus and accessory muscles of the pelvis, with unusually large calf muscles. The physician suspects a genetic disease and refers the patient to genetic testing.  Which of the following DNA sequences is most likely present in this patient?


Normal Sequence: GGC TAC GTG AAG AAG TCT
Normal DNA Sequence:  
|Explanation=The patient in this vignette is suffering from Duchenne Muscular Dystrophy.  Duchenne muscular dystrophy (DMD) is a recessive X-linked form ofmuscular dystrophy, affecting around 1 in 3,600 boys, which results in muscle degeneration and eventual death.  The disorder is caused by a mutation in the dystrophin gene, the largest gene located on the human X chromosome, which codes for the protein dystrophin, an important structural component within muscle tissue.  Typically, it becomes harder and harder for the boy to walk; his ability to walk usually completely disintegrates between the time the boy is 9 to 12 years of age. Most men affected with DMD become essentially “paralyzed from the neck down” by the age of 21.[10] Muscle wasting begins in the legs and pelvis, then progresses to the muscles of the shoulders and neck, followed by loss of arm muscles and respiratory muscles. Calf muscle enlargement (pseudohypertrophy) is quite obvious.  Children often display a positive Gower’s sign (link).
5'...GGC TAC GTG AAG AAG TCT...3'
3'...CCG ATG CAC TTC TTC AGA...5'
|Explanation=Duchenne muscular dystrophy (DMD) is a recessive X-linked form of muscular dystrophy, affecting around 1 in 3,600 boys, which results in muscle degeneration and eventual death.  The disorder is caused by a mutation in the dystrophin gene, the largest gene located on the human X chromosome, which codes for the protein dystrophin, an important structural component within muscle tissue.  Typically, it becomes harder and harder for the boy to walk; his ability to walk usually completely disintegrates between the time the boy is 9 to 12 years of age. Most men affected with DMD become essentially “paralyzed from the neck down” by the age of 21.[10] Muscle wasting begins in the legs and pelvis, then progresses to the muscles of the shoulders and neck, followed by loss of arm muscles and respiratory muscles. Calf muscle enlargement (pseudohypertrophy) is quite obvious.  Children often display a positive Gower’s sign (link).


The DMD gene consists of 79 exons, making it one of the largest genes in the genome.  While many thousands of mutations in the DMD gene have been observed, the majority of patients (~70%) harbor deletions of the gene.  We know that the patient does not exhibit any structural changes in the gene, so the patient more likely has a mutation causing dysfunctional Dystophin protein.  The most likely mutation to cause DMD in this patient is the nonsense mutation in C.  Nonsense mutations are caused by the insertion of a premature stop codon.  The following codons are stop codons
The DMD gene consists of 79 exons, making it one of the largest genes in the genome.  While many thousands of mutations in the DMD gene have been observed, the majority of patients (~70%) harbor deletions of the gene.  We know that the patient does not exhibit any structural changes in the gene, so the patient more likely has a mutation causing dysfunctional Dystophin protein.  The most likely mutation to cause DMD in this patient is the nonsense mutation in C.  Nonsense mutations are caused by the insertion of a premature stop codon.  The following codons are stop codons
Line 36: Line 38:
UGA (U Go Away)
UGA (U Go Away)
UAG (U Are Gone)
UAG (U Are Gone)
|AnswerA=GGC TAC GTA AAG AAG TCT
|AnswerA=5'...GGC TAC GTA AAG AAG TCT...3'
|AnswerAExp=This sequence reflects a missense mutation, which is not usually a cause of [[Duchenne Muscular Dystrophy]].
|AnswerAExp=This sequence reflects a missense mutation, which is not usually a cause of [[Duchenne Muscular Dystrophy]].
|AnswerB=GGT ACG TGA AGA AGA TCT
|AnswerB=5'...GGT ACG TGA AGA AGA TCT...3'
|AnswerBExp=The above sequence actually comprises two mutations.  One mutation from GGC T -> GGT reflects a one base pair deletion.  The other is a one base pair insertion after AAG AAG T... -> AAG AAG AT... . Thus, the first mutation disrupts the frame of the sequence and the second mutation restores it. The above sequence thus reflects 5 missense mutations with no nonsense mutations. The series of two mutations is extremely unlikely and the nature of the mutations is unlikely to be severe enough to cause Duchenne Muscular Dystrophy.
|AnswerBExp=This sequence comprises two mutations: One mutation from "5'...GGC T to GGT...3'" reflects a one base pair deletion; while the other is a one base pair insertion after 5'...AAG AAG T to AAG AAG AT...3'. The first mutation disrupts the frame of the sequence whereas the second mutation restores it. The above sequence thus reflects 5 missense mutations with no nonsense mutations. The series of two mutations is extremely unlikely and does not explain the genetic disorder observed in Duchenne muscular dystrophy.
|AnswerC=GGC TAA GTG AAG AAG TCT
|AnswerC=5'...GGC TAA GTG AAG AAG TCT...3'
|AnswerCExp=This mutation reflects the insertion of an inappropriate stop codon (TAC-> TAA) and is therefore a nonsense mutation.
|AnswerCExp=This mutation reflects the insertion of an inappropriate stop codon 5'...TAC to TAA...3'. mRNA transcription of this sequence will be: 5'...GGC UAA GUG AAG AAG UCU...3'. The second trinucleotide UAA is a stop codon, which does not correspond to any amino acid. It leads to the formation of a truncated dystrophin protein.
|AnswerD=GGC TAC GTG ATG AAG TCT
|AnswerD=5'...GGC TAC GTG ATG AAG TCT...3'
|AnswerDExp=This sequence reflects a missense mutation, which is not usually a cause of Duchenne Muscular Dystrophy.
|AnswerDExp=This sequence reflects a missense mutation, which is not usually a cause of Duchenne muscular dystrophy.
|AnswerE=GGC TAC GTG AAG AAG AAG ...(x20)... TCT
|AnswerE=5'...GGC TAC GTG AAG AAG AAG...(x20)...TCT...3'
|AnswerEExp=This mutation would be a repeat expansion, which is the cause of [[Huntington’s disease]] and not [[Duchenne Muscular Dystrophy]].
|AnswerEExp=This mutation reveals a trinucleotide repeat expansion. Generally, repeat expansions are identified among patients with [[Huntington’s disease]] (CAG), Fragile X syndrome (CGG), Friedreich ataxia (GAA), and myotonic dystrophy (CTG). [[Duchenne muscular dystrophy]] is not a trinucleotide repeat expansion disease.
|EducationalObjectives=UAA is a stop codon. Premature stop codons are referred to as nonsense mutations and often lead to the production of a dysfunctional gene product.
|EducationalObjectives=UAA is a stop codon. Premature stop codons are referred to as nonsense mutations and often lead to the production of a truncated protein. Duchenne muscular dystrophy is a genetic disorder characterized by the frameshift mutation due to insertion of a base pair that converts the coding of a normal amino acid into a stop codon.
|References=First Aid 2014 page 89; First Aid 2012 page 91
|References=First Aid 2014 page 89; First Aid 2012 page 91
|RightAnswer=C
|RightAnswer=C

Revision as of 19:44, 2 September 2014
Author [[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type ExamType::USMLE Step 1
Main Category MainCategory::Genetics
Sub Category SubCategory::Musculoskeletal/Rheumatology
Prompt [[Prompt::A 10-year-old boy is brought to the pediatrician's office by his mother for chronic weakness. She reports that her child started to have trouble rising from chairs at the age of six. He has become progressively weaker over the past four years and now requires braces to walk. Physical examination is remarkable for proximal weakness of the upper and lower extremities. The pediatrician also notes atrophy of the gluteus maximus and accessory muscles of the pelvis, with unusually large calf muscles. The physician suspects a genetic disease and refers the patient to genetic testing. Which of the following DNA sequences is most likely present in this patient?

Normal DNA Sequence: 5'...GGC TAC GTG AAG AAG TCT...3' 3'...CCG ATG CAC TTC TTC AGA...5']]

Answer A AnswerA::5'...GGC TAC GTA AAG AAG TCT...3'
Answer A Explanation [[AnswerAExp::This sequence reflects a missense mutation, which is not usually a cause of Duchenne Muscular Dystrophy.]]
Answer B AnswerB::5'...GGT ACG TGA AGA AGA TCT...3'
Answer B Explanation [[AnswerBExp::This sequence comprises two mutations: One mutation from "5'...GGC T to GGT...3'" reflects a one base pair deletion; while the other is a one base pair insertion after 5'...AAG AAG T to AAG AAG AT...3'. The first mutation disrupts the frame of the sequence whereas the second mutation restores it. The above sequence thus reflects 5 missense mutations with no nonsense mutations. The series of two mutations is extremely unlikely and does not explain the genetic disorder observed in Duchenne muscular dystrophy.]]
Answer C AnswerC::5'...GGC TAA GTG AAG AAG TCT...3'
Answer C Explanation [[AnswerCExp::This mutation reflects the insertion of an inappropriate stop codon 5'...TAC to TAA...3'. mRNA transcription of this sequence will be: 5'...GGC UAA GUG AAG AAG UCU...3'. The second trinucleotide UAA is a stop codon, which does not correspond to any amino acid. It leads to the formation of a truncated dystrophin protein.]]
Answer D AnswerD::5'...GGC TAC GTG ATG AAG TCT...3'
Answer D Explanation AnswerDExp::This sequence reflects a missense mutation, which is not usually a cause of Duchenne muscular dystrophy.
Answer E AnswerE::5'...GGC TAC GTG AAG AAG AAG...(x20)...TCT...3'
Answer E Explanation [[AnswerEExp::This mutation reveals a trinucleotide repeat expansion. Generally, repeat expansions are identified among patients with Huntington’s disease (CAG), Fragile X syndrome (CGG), Friedreich ataxia (GAA), and myotonic dystrophy (CTG). Duchenne muscular dystrophy is not a trinucleotide repeat expansion disease.]]
Right Answer RightAnswer::C
Explanation [[Explanation::Duchenne muscular dystrophy (DMD) is a recessive X-linked form of muscular dystrophy, affecting around 1 in 3,600 boys, which results in muscle degeneration and eventual death. The disorder is caused by a mutation in the dystrophin gene, the largest gene located on the human X chromosome, which codes for the protein dystrophin, an important structural component within muscle tissue. Typically, it becomes harder and harder for the boy to walk; his ability to walk usually completely disintegrates between the time the boy is 9 to 12 years of age. Most men affected with DMD become essentially “paralyzed from the neck down” by the age of 21.[10] Muscle wasting begins in the legs and pelvis, then progresses to the muscles of the shoulders and neck, followed by loss of arm muscles and respiratory muscles. Calf muscle enlargement (pseudohypertrophy) is quite obvious. Children often display a positive Gower’s sign (link).

The DMD gene consists of 79 exons, making it one of the largest genes in the genome. While many thousands of mutations in the DMD gene have been observed, the majority of patients (~70%) harbor deletions of the gene. We know that the patient does not exhibit any structural changes in the gene, so the patient more likely has a mutation causing dysfunctional Dystophin protein. The most likely mutation to cause DMD in this patient is the nonsense mutation in C. Nonsense mutations are caused by the insertion of a premature stop codon. The following codons are stop codons DNA: TAA TGA TAG

RNA: UAA (U Are Away) UGA (U Go Away) UAG (U Are Gone)
Educational Objective: UAA is a stop codon. Premature stop codons are referred to as nonsense mutations and often lead to the production of a truncated protein. Duchenne muscular dystrophy is a genetic disorder characterized by the frameshift mutation due to insertion of a base pair that converts the coding of a normal amino acid into a stop codon.
References: First Aid 2014 page 89; First Aid 2012 page 91]]

Approved Approved::Yes
Keyword WBRKeyword::Muscle, WBRKeyword::Muscular Dystrophy, WBRKeyword::Mutation, WBRKeyword::Gene, WBRKeyword::Nucleotide, WBRKeyword::Genetics, WBRKeyword::Weakness
Linked Question Linked::
Order in Linked Questions LinkedOrder::
Retrieved from "https://www.wikidoc.org/index.php?title=WBR0099&oldid=1015947"