gene discovery in a smooth muscle disorder could have “profound implications for all of genetics”
most of what we know about dna is focused on just two per cent of the genome. exciting new research is shedding light on the other 98 per cent.
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clinicians at massachusetts general hospital’s undiagnosed diseases network say they have connected a mutation in a poorly understood area of the genome to the rare disorder called multisystemic smooth muscle dysfunction syndrome (msmds).
shedding light on this area of the genetic code could have “profound implications for all of genetics,” explains co-author david sweetser, chief of medical genetics and metabolism at massachusetts general hospital (mgh).
multisystemic smooth muscle dysfunction syndrome (msmds) impairs the function of the muscles integral to the “hollow organs” in the body — like the stomach, intestines and blood vessels. for a 16-year-old patient who found himself at mgh, this resulted in frequent strokes since the age of three, feeding issues, and complications with his bowel and bladder.
researchers looked for genetic mutations in the patient that were already documented to cause msmds but did not find a mutation in this region. it was when they zoomed out to lesser-known areas of the genome, known as non-coding regions, that they found something interesting.
“we came up with a very intriguing change that was appeared to be a mutation in a gene that was brand new — not seen in his parents … it was a gene called a micro-rna, that doesn’t encode proteins,” explains sweetser. “… we were able to not only verify that this mutation can cause this same syndrome but, in the process, were able to identify this as one of one of the very rare cases that have been discovered so far of these non-coding gene mutations that cause human disease.”
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non-coding genes the next frontier in genetics
non-coding regions of dna make up roughly 98 per cent of the human genome, according to the national human genome research institute. unlike the coding regions of dna, this vast area of our genome doesn’t directly encode for the proteins that make up virtually every aspect of our bodies. instead, these regions play a role in helping mechanisms in the body identify when and where it needs to use the coding regions of the dna to make proteins. it likely has other roles, however, what these are is difficult to say.
“[coding regions] are just low hanging fruit, because it’s easy to interpret,” explains ryan yuen, senior scientist in the genetics and genome biology program at the hospital for sick children. “what’s challenging is the rest of the cases where do not have any mutations found in the coding regions.” (yuen was not part of the study at mgh.)
at one point these non-coding regions were even dubbed “junk dna,” as their purpose eluded geneticists. advances in technology is making it easier to sequence the entire genome, so the race is on to determine how these sections could play a role in disease.
“it’s a really huge challenge to understand what all of this so-called dark matter is doing,” say sweetser.
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currently, the number of genetic conditions linked to non-coding regions of the cell are very small, with mgh estimating only six other such discoveries being made.
gene secrets unravelled by a team of experts
once the team had identified the nature of the boy’s illness, they sequenced his entire dna — not just the coding regions typically sequenced in a genetic analysis. a coding gene, acta2, has already been associated with preventing smooth muscles in the body from working properly, but in this case the acta2 gene appeared to be mutation-free.
what they did find was a singe mutation in a gene called mir145-5p. mir145-5p doesn’t encode for a particular protein itself but impacts how several other coding regions of dna are translated into proteins. these proteins, in turn, play a role in how smooth muscle cells function.
the research, published the journal of clinical investigation, will also help improve the boy’s treatment plan, which before was focused on handling inflammation. knowledge of the specific proteins that are affected by this genetic mutation means more targeted approached to managing blood pressure and other procedures.
on top of more targeted treatment plans, a deeper understanding of these conditions may also pave the way to future genetic therapies or protein replacement therapies.
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emma jones is a multimedia editor with healthing. you can reach her at emjones@postmedia.com or on instagram and twitter @jonesyjourn.
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