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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor=William J Gibson
|QuestionAuthor=William J Gibson (Reviewed by  {{YD}})
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Biochemistry, Genetics
|MainCategory=Genetics
|SubCategory=General Principles
|SubCategory=Musculoskeletal/Rheumatology
|MainCategory=Biochemistry, Genetics
|MainCategory=Genetics
|SubCategory=General Principles
|SubCategory=Musculoskeletal/Rheumatology
|MainCategory=Biochemistry, Genetics
|MainCategory=Genetics
|SubCategory=General Principles
|SubCategory=Musculoskeletal/Rheumatology
|MainCategory=Biochemistry, Genetics
|MainCategory=Genetics
|MainCategory=Biochemistry, Genetics
|MainCategory=Genetics
|SubCategory=General Principles
|MainCategory=Genetics
|MainCategory=Biochemistry, Genetics
|SubCategory=Musculoskeletal/Rheumatology
|SubCategory=General Principles
|MainCategory=Genetics
|MainCategory=Biochemistry, Genetics
|SubCategory=Musculoskeletal/Rheumatology
|SubCategory=General Principles
|MainCategory=Genetics
|MainCategory=Biochemistry, Genetics
|SubCategory=Musculoskeletal/Rheumatology
|SubCategory=General Principles
|MainCategory=Genetics
|MainCategory=Biochemistry, Genetics
|SubCategory=Musculoskeletal/Rheumatology
|MainCategory=Biochemistry, Genetics
|MainCategory=Genetics
|SubCategory=General Principles
|MainCategory=Genetics
|Prompt=A 10 year old boy with a long history of chronic weakness is brought to a new pediatricians office by his mother seeking a new diagnosis for her son. She reports that around the age of six, the boy began having trouble rising from chairs. He has grown progressively weaker over the past four years and now requires braces to walk. Physical exam shows weakness of the legs, and arms most notably, the proximal muscles. The pediatrician notes atrophy of the gluteus maximus and accessory muscles of the pelvis, yet unusually large calf muscles. The family had previously ordered genetic testing, although structural analysis of the candidate gene revealed no abnormalities.  Which of the following mutations, if any would you most likely expect in the gene which was previously examined?
|SubCategory=Musculoskeletal/Rheumatology
|Prompt=A 8-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 running and rising from chairs at the age of 5. He has become progressively weaker over the past 3 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 mRNA 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).
<br>5'...GGC TAC GTG AAG AAG TCT...3'
<br>3'...CCG ATG CAC TTC TTC AGA...5'
|Explanation=[[Duchenne muscular dystrophy]] (DMD) is a recessive X-linked genetic disease that affects 1 in 3500-6000 live male births. The disorder is caused by a mutation in the ''dystrophin'' gene, which is the largest human gene comprised of 2.6 million base pairs of DNA and 79 exons. The majority of dystrophin mutations are due to [[frameshift mutation]]s by deletions or insertions, but point mutations have also been described among patients with DMD. ''Dystrophin'' gene normally encodes the [[dystrophin protein]], a major structural protein that links the internal [[cytoskeleton]] of  muscle cells to the [[extracellular matrix]]. Most patients with DMD lack any [[dystrophin protein]].


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 majority of patients with DMD are diagnosed at approximately the age of 5 years. Clinical features include delayed motor milestones, inability to run, jump, or physically compete with peers at school due to progressive weakness of the proximal muscles, such as the hip abductors and the quadriceps. Additionally, patients are unable to arise from the floor, showing the classical Gower's maneuver. On physical examination, patients typically have proximal muscle weakness with atrophy of large muscles, such as the [[gluteus maximus]] muscle, and [[pseudohypertrophy]] of the calves due to replacement of muscles by fibrofatty tissue. Most patients are wheelchair-bound by the age of 12-13, and die by the age of 18-20 years due to [[respiratory failure]].
DNA:
TAA
TGA
TAG


RNA:
The most likely mutation to cause DMD is a deletion/insertion that leads to frameshift error downstream by creating a [[stop codon]]. It is important to remember that DNA has 2 strands: 5' to 3' (sense strand) and a complementary 3' to 5' (anti-sense strand). The 3' to 5' DNA strand (anti-sense strand) is the one that is transcribed by mRNA; and mRNA is read from 5' to 3'. Accordingly, the mRNA will have a complementary sequence to the 3' to 5' antisense strand, but an identical sequence to the 5' to 3' sense strand, with the exception of having [[uracil]] (U) replacing every [[thymine]] (T). In humans, only 3 mRNA codons are stop codons: UAA, UGA, and UAG.
UAA (U Are Away)
|AnswerA=5'...GGC TAC GTA AAG AAG TCT...3'
UGA (U Go Away)
|AnswerAExp=This sequence reflects a [[missense mutation]], which is not usually a common cause of [[Duchenne muscular dystrophy]].
UAG (U Are Gone)
|AnswerB=5'...GGT ACG TGA AGA AGA TCT...3'
|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...3' to 5'...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 commonly explain the genetic disorder observed in Duchenne muscular dystrophy.
|AnswerC=5'...GGC TAA GTG AAG AAG TCT...3'
|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=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.
|AnswerE=5'...GGC TAC GTG AAG AAG AAG...(x20)...TCT...3'
|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 an mRNA stop codon. Premature stop codons are referred to as nonsense mutations and often lead to the production of a truncated proteins. 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, resulting in the formation of a truncated dystrophin protein.
|References=Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010;9(1):77-93.


Educational Objective: 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.
Nowak KJ, Davies KE. Duchenne muscular dystrophy and dystrophin: pathogenesis and opportunities for treatment. EMBO Rep. 2004;5(9):872-6


References: First Aid 2012 page 91
First Aid 2014 page 89
Tags:  #Genetics #Musculoskeletal
|AnswerA=GGC TAC GTA AAG AAG TCT
|AnswerAExp=Incorrect - This sequence reflects a missense mutation, which is not usually a cause of Duchenne Muscular Dystrophy.
|AnswerB=GGT ACG TGA AGA AGA TCT
|AnswerBExp=Incorrect - 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.
|AnswerC=GGC TAA GTG AAG AAG TCT
|AnswerCExp=Correct - This mutation reflects the insertion of an inappropriate stop codon (TAC-> TAA) and is therefore a nonsense mutation.
|AnswerD=GGC TAC GTG ATG AAG TCT
|AnswerDExp=Incorrect- 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
|AnswerEExp=Incorrect - This mutation would be a repeat expansion, which is the cause of Huntingtin’s disease and not Duchenne Muscular Dystrophy.
|RightAnswer=C
|RightAnswer=C
|WBRKeyword=Muscle, Muscular Dystrophy, mutation, gene, nucleotide, genetics, weakness, Duchenne muscular dystrophy, Duchenne Muscular Dystrophy, frameshift mutation, frameshift, DNA, mrNA, RNA, template, strand, sense, antisense, antisense, DNA strand, mRNA strand, complement
|Approved=Yes
|Approved=Yes
}}
}}

Latest revision as of 23:20, 27 October 2020
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 8-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 running and rising from chairs at the age of 5. He has become progressively weaker over the past 3 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 mRNA 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 common 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...3' to 5'...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 commonly 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 genetic disease that affects 1 in 3500-6000 live male births. The disorder is caused by a mutation in the dystrophin gene, which is the largest human gene comprised of 2.6 million base pairs of DNA and 79 exons. The majority of dystrophin mutations are due to frameshift mutations by deletions or insertions, but point mutations have also been described among patients with DMD. Dystrophin gene normally encodes the dystrophin protein, a major structural protein that links the internal cytoskeleton of muscle cells to the extracellular matrix. Most patients with DMD lack any dystrophin protein.

The majority of patients with DMD are diagnosed at approximately the age of 5 years. Clinical features include delayed motor milestones, inability to run, jump, or physically compete with peers at school due to progressive weakness of the proximal muscles, such as the hip abductors and the quadriceps. Additionally, patients are unable to arise from the floor, showing the classical Gower's maneuver. On physical examination, patients typically have proximal muscle weakness with atrophy of large muscles, such as the gluteus maximus muscle, and pseudohypertrophy of the calves due to replacement of muscles by fibrofatty tissue. Most patients are wheelchair-bound by the age of 12-13, and die by the age of 18-20 years due to respiratory failure.

The most likely mutation to cause DMD is a deletion/insertion that leads to frameshift error downstream by creating a stop codon. It is important to remember that DNA has 2 strands: 5' to 3' (sense strand) and a complementary 3' to 5' (anti-sense strand). The 3' to 5' DNA strand (anti-sense strand) is the one that is transcribed by mRNA; and mRNA is read from 5' to 3'. Accordingly, the mRNA will have a complementary sequence to the 3' to 5' antisense strand, but an identical sequence to the 5' to 3' sense strand, with the exception of having uracil (U) replacing every thymine (T). In humans, only 3 mRNA codons are stop codons: UAA, UGA, and UAG.
Educational Objective: UAA is an mRNA stop codon. Premature stop codons are referred to as nonsense mutations and often lead to the production of a truncated proteins. 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, resulting in the formation of a truncated dystrophin protein.
References: Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010;9(1):77-93.

Nowak KJ, Davies KE. Duchenne muscular dystrophy and dystrophin: pathogenesis and opportunities for treatment. EMBO Rep. 2004;5(9):872-6

First Aid 2014 page 89]]

Approved Approved::Yes
Keyword WBRKeyword::Muscle, WBRKeyword::Muscular Dystrophy, WBRKeyword::mutation, WBRKeyword::gene, WBRKeyword::nucleotide, WBRKeyword::genetics, WBRKeyword::weakness, WBRKeyword::Duchenne muscular dystrophy, WBRKeyword::Duchenne Muscular Dystrophy, WBRKeyword::frameshift mutation, WBRKeyword::frameshift, WBRKeyword::DNA, WBRKeyword::mrNA, WBRKeyword::RNA, WBRKeyword::template, WBRKeyword::strand, WBRKeyword::sense, WBRKeyword::antisense, WBRKeyword::antisense, WBRKeyword::DNA strand, WBRKeyword::mRNA strand, WBRKeyword::complement
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