USMLE® Step 1 style questions USMLE
USMLE® Step 2 style questions USMLE
A 2-year-old African American boy comes to his pediatrician's office because of loose and stretchy skin for the past year. His mother reports that his skin appears very thick and dark. The patient's past medical history is significant for developmental delay and failure to thrive. Physical examination shows large lips, broad mouth, and a high forehead. The child is happy and playful. Skin examination shows deep creases in the palms and soles, thickened skin, and curly sparse hair.
Which of the following genetic defects is most likely responsible for this patient's symptoms?
Content Reviewers:Rishi Desai, MD, MPH
Now, it happens when a gene on chromosome 15 called UBE3A is not expressed, or transcribed into messenger RNA.
UBE3A stands for ubiquitin-protein ligase E3A, and the protein it codes for is called E6AP or E6-associated protein.
The job of E6AP is to go around tagging, or attaching, a tiny protein called ubiquitin to other proteins, a process called ubiquitination.
Once that happens, the ubiquitinated protein is degraded by the proteasome, a part of the cell’s recycling machinery.
It’s kind of painting an orange U on a tree so that a lumberjack knows to chop it down.
So E6 associated protein has an important job, and it turns out that the region of chromosome 15 around UBE3A is imprinted, imprinting refers to gene expression that’s dependent on the parent of origin of a gene.
This means that either the maternally derived or paternally derived copy of the gene is silenced.
This differs from most genes in the genome, where both the maternal and paternal copies are expressed.
Normally, in the brain, only the maternally derived copy of UBE3A is expressed, while the paternal copy is silenced, unfortunately this process of imprinting leaves the maternal copy of UBE3A vulnerable.
So with the paternal copy of the gene imprinted, and epigenetically silenced, you’ve only got the maternal copy left.
So this means that if anything happens to the maternal copy, the result is Angelman syndrome.
There are a few different types of mutations that can cause Angelman syndrome.
The most common one is a deletion of a couple million base pairs of DNA on the maternal copy of chromosome 15 which includes UBE3A.
Sometimes the deletion overlaps a nearby gene called OCA2, which codes for a pigment that gives color to eye, hair, and skin.
As a result of this, these Angelman syndrome patients can have a light complexion.
A second way is a mutation within the maternal copy of UBE3A, making the protein ineffective.
A third way to get Angelman syndrome is when the entire maternal chromosome 15 is absent and instead there’s an extra copy of the paternal chromosome 15.
This scenario is called paternal uniparental disomy, which means that one parent – the father – contributed two of the same chromosome while the mother contributed none.