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Pathogenic Genetic Mutations That Cause Sleep Syndromes

Discussion in 'Sleep' started by BeautifulDay, Mar 24, 2018.

  1. BeautifulDay

    BeautifulDay Senior Member

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    As human beings we are extremely complex. “The universe of genes that are actually expressed in humans—called the exome—is comprised of about 30 million bases of DNA.” There are 3 billion base pairs in the human genome.
    https://www.forbes.com/sites/quora/...e-combinations-of-dna-are-there/#efcba0d5835d
    https://www.genome.gov/11006943/human-genome-project-completion-frequently-asked-questions/

    Apart from my family’s mitochondrial disease, we also have trouble with our sleep. The family pattern is often different than those around us. My body clock likes to drop off early, wake in the middle of the night for a few hours, and then get back to sleep and then up early. Today I was out of bed at 4:00 a.m.

    It’s very easy to attribute all weirdness (symptoms) to lack of mitochondrial energy because without energy anything and everything can go haywire. At the same time, other mutations can lead to complex issues due to a variant or a combination of a different variant and the mitoD. That brings me to my mind wandering into genetic sleep variants.

    The PER1, PER2, and PER3 genes are all known to have a significant impact on sleep.

    First mutation
    One of our children has the dominant pathogenic missense mutation on the PER3 gene -- rs150812083 that causes FAMILIAL ADVANCED SLEEP PHASE SYNDROME 3 (FASPS3). It’s rare (occurring in less than 1% of the population). This mutation is considered dominant (if one has received a copy from one parent, then they will have the syndrome). Yet even though it’s called dominant, I believe it’s only been known to be inherited with the Pathogenic mutation rs139315125. Our child also has both pathogenic mutations.
    https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=150812083
    https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=139315125

    Study on these mutations:
    “RESULTS:
    Affected members rated themselves as "morning types" and had a significant advance in the phase of sleep onset (P<.001) and offset (P =.006) times. The mean sleep onset was 2121 hours for the affected family members and 0025 hours for the unaffected family members. The mean sleep offset was 0507 hours for the affected members and 0828 hours for the unaffected members. (Times are given in military form.) In addition, the phase of the circadian rhythm of melatonin onset for the affected family members was on average 3-1/2 hours earlier than for the unaffected members.
    CONCLUSIONS:
    The ASPS trait segregates with an autosomal dominant mode of inheritance. The occurrence of familial ASPS indicates that human circadian rhythms, similar to those in animals, are under genetic regulation. Genetic analysis of familial sleep and circadian rhythm disorders is important for identifying a specific gene(s) responsible for the regulation of sleep and circadian rhythms in humans.”
    https://www.ncbi.nlm.nih.gov/pubmed/11448298

    Both mutations must have been inherited from my x-husband and his family since I carry neither. He is an early riser and his father was an extremely early riser (with early to bed). None of them were known to have two phased sleep. As far as I can remember, both slept very well through the entire night.

    Second mutation
    I have a different deleterious mutation. This one is on the PER1 gene. rs12937495. https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=12937495

    It is rare (occurring in less than 1% of the population), it’s in a highly conserved area across species, it’s a missense mutation, and it’s thought by scientists to be severely deleterious. The problem is that when doing these small sleep studies, it has yet to pop up in their small sample population due to it’s rarity. Therefore, while there are examples of families like our own with the sleep syndrome in those who carry it (combined early sleep and wake cycles with two phased sleep), more families need to be studied before it’s changed from deleterious to pathogenic.

    In the study titled “A silent polymorphism in the PER1 gene associates with extreme diurnal preference in humans”, the researchers were looking for various PER1 mutations (including rs12937495) in a small pool of troubled sleepers. Due to the small pool, our variant was not found in this sample. But it is interesting to note that researchers are looking for people with such mutations. NIH estimates this mutation at .0018 of the population.
    https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?geneId=5187
    https://www.researchgate.net/public...tes_with_extreme_diurnal_preference_in_humans

    My mother is also like me in that she has two phased sleep and is up long before the sunrise.

    Meandering
    We had initially thought all our sleep issues were due to MitoD. Yet, clearly there is more involved here.

    We have one child with no known sleep mutations on the PER1, PER2, and PER3 genes. Yet, this child will often rise of own accord on weekends at 6:00a.m. or 7:00 a.m. This child does not have two phased sleep patterns. Then again, I get this child to bed early due to my need to go to sleep early. So it could be her sleep cycle from environment.

    On the other hand, the child with both the PER1 mutation and the PER3 mutation is often visiting me or texting me in the middle of the night (“Are you awake?”). And of course I am. Thankfully, this child will never be told like I was by doctors that it’s my own fault that I have odd sleeping habits. Patient blaming rather than actually listening.

    Per the first link in this post from Forbes, there are “60 novel mutations in every living human being. There are 7 billion humans, so we know that some 420 billion different variants are possible. And that is just the number of new changes that arise in a single generation. The number passed down and recombined from previous generations is much larger.” Therefore, with human beings having an infinite set of variant combinations, it’s time that doctors stop telling us when we come into their offices with very odd symptoms that such symptoms are impossible and it must be all our fault and likely in our heads.
     
    Last edited: Mar 24, 2018

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