delayed sleep phase disorder

choi

On Aug 5, 2021 the SundayStyes section of New York Times had a lookback on four past writers of its Modern Love column. One of them was

They Really Are as Different as Night and Day; A writer led a nocturnal life, but then she fell in love.
https://www.nytimes.com/2021/08/ ... -amanda-gefter.html

Note:
(a) Online: "Below is my conversation with Ms Gefter, whose episode stars Zoë Chao and Gbenga Akinnagbe. The interview has been edited for length and clarity."
In print: The sentence ended at "edited" (and the paragraph following this online sentence, promoting three other writers, did ot appeal  in print, either).

"whose episode stars Zoë Chao and Gbenga Akinnagbe"?  New York Times wants to milk more money out of the long-ago essay, by creating episodes in Amazon Prime Video so that people will pay to watch a fictional video based on the ess

The rest is about delayed sleep phase disorder (DSPD).

(b) You may guess correctly that delayed sleep phase disorder is autosomal dominant.
(c) Discoveries of Molecular Mechanisms Controlling the Circadian Rhythm, Nobel Prize in Physiology or Medicine, 2017
https://www.nobelprize.org/prize ... vanced-information/
("is awarded to Jeffrey C Hall, Michael Rosbash and Michael W Young * * * mimosa [含羞草属]")

On this same Web page, please click atop the title
"Scientific Background:
Discoveries of Molecular Mechanisms Controlling the Circadian Rhythm (pdf)."

Click it.

The genes responsible for circadian cycle -- their mutations changed circadian cycle, that was how they were discovered; various mutations of anyone of those genes may lengthen, shorten or lose (turn arrhythmic) cycle -- are mostly first discovered in fruit fly: period (PER), timeless (TIM), doubletime (DBT), and cycle (CYC).  The gene cryptochrome (CRY), encoding a photoreceptor, was discovered in plant (actually there are two similar genes: CRY1 and CRY2). The clock (CLK) gene was first found in mouse.  

The circadian cycle (from fruit fly to plant to human) are summarized in Fig 2 B. CLK and CYC are two transcription factors that transcribe (meaning: make RNA) the period gene. The period protein then couples with TIM protein to suppress transcription of the period gene, in a process called feedback; this feedback creates a self-sustainable cycle (which is slightly longer than 24 hours in each cycle) if the organism is housed in total darkness for a long time. The purpose of light is to adjust the circadian cycle according to the light cycle (which may or may not be 24 hours a cycle). In the presence of light:
• DBT protein adds phosphate ion to period protein, accelerating the destruction of the period protein; and
• CRY protein binds to TIM, destining the latter protein for destruction.
Without suppression from PER and TIM, transcription of the period gene resumes (and the organism returns to the previous, innate cycle).

Take notice that the cycle gene is called BMAL1 gene in mammalian, which was discovered earlier under a different circumstance.

(c) Patke A et al (from Michael W Young's lab), Mutation of the Human Circadian Clock Gene CRY1 in Familial Delayed Sleep Phase Disorder. Cell, 169: 203 (2018)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479574/

Results: "The patient in the research sleep in the lab for observation. [Her going to bed] occurred at 2:32 am, well after the time expected in a subject of normal chronotype (typically between 8 to 10 pm) * * * The resulting gross sleep/wake rhythm [of a DSPD patient in their research] had a period of 24.5 hours * * * By contrast, the 24.2-hour period length of a control subject [also in their research] undergoing the same protocol matches the intrinsic period length reported for normal human subjects * * * [The patient has A to C mutation at the 5' splice site following exon 11 of one of the two CRY1 genes (one from father and the other from mother), causing 'exon skipping']

Discussion: "Our results show that the CRY1 DSPD allele represents a gain-of-function mutation with deletion of exon 11 leading to increased CRY1 nuclear localization, enhanced interaction with the transcription factors Clock and Bmal1, their displacement from chromatin and heightened inhibition of their target genes.

What the discussion said is that the patient's CRY1 protein lacks the sequence encoded by exon 11. The resulting CRY1 protein gains function by clinging more tightly to and removing the two transcription factors CLK and Bmal1, reducing period transcription. * * * Accordingly [two earlier reports indicated change in circadian cycle affects sleep timing], a half hour change in the period of the human circadian clock is expected to change the relationship of sleep timing and evening melatonin onset (DLMO) by ~2–2.5 hours.

•  there is no need to read the rest of this research report.