ColQ: a Collagen-Like Protein

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Lisa Sanders, Stair Case. She was told she had untreatable muscular disorder. Thirty years later, she decided to have more testing done. New York Times Magazine, June 8, 2024, at page 18.
https://www.nytimes.com/2024/06/ ... rome-diagnosis.html

Note:
(a)
(i) Mary-Lynn Y Chu, MD
("Pediatric Neurology
Treats: Children
Language: English
* * *
Credentials
positions  Clinical Professor, Department of Neurology at NYU Grossman School of Medicine
Board Certifications  American Board of Psychiatry & Neurology - w/Spec Qual's [with Special Qualification] In Child Neurolo[gy], 1991
Education and Training
Fellowship, Hospital for Special Surgery, Neuromuscular Diseases, 1990
Fellowship, Albert Einstein College of Medicine, Pediatric Neurology, 1989
Residency, Albert Einstein College of Medicine, 1986
Residency, University of the Philippines, 1983
MD from University Of Philippines, 1978")

My research shows she was born in April 1954 (50 years old, despite her apparently black hair), has maiden name Dronsick, and has held a medical license from New York State since 1985.
(ii) Press release: Dr John Pappas Celebrates 35 Years in Medicine. Marquis Who's Who Ventures LLC, May 4, 2020
https://www.24-7pressrelease.com ... 5-years-in-medicine
("Dr John Pappas has been included in Marquis Who's Who. * * * He studied at the University of Athens in Greece, from which he attained a Doctor of Medicine in 1985, after which he undertook an internship and residency in pediatrics at Beth Israel Medical Center, NY. Subsequently serving as the chief resident of pediatrics, he served two years in the Greek Navy. He came back to the US after the naval service. He married the prominent NYC pediatrician Dr. Camille Senzamici who he met during residency. He completed a fellowship in clinical genetics at Mount Sinai Medical Center, NY. Dr. Pappas presently excels as the director of clinical genetic services at NYU Langone Medical Center")
(A) The Greek surname Pappas is "variant of [Greek surname] Papas 'priest.' Compare Pappa."

Modern Greek-English dictionary:
* Παππάς (romanization Pappás) "is a Greek surname, which means 'priest.' "  en.wikipedia.org for Pappas.
* παπάς (noun masculine; romanization papás; etymology: "honorific for priests * * * from Ancient Greek πάππας páppas, 'children's language for grandfather.' Doublet of πάπας pápas, 'the pope' "): "(religion) Eastern Orthodox and Roman Catholic priest"
https://en.wiktionary.org/wiki/παπάς
(B) The Italian (southern) surname Pappa is a "nickname for a greedy or voracious person * * * from pappa 'he eats' from pappare 'to munch or gobble' * * * [The same spelling can also be] Italian (southern) [surname]: possibly also a variant of Papa 'father cleric pope’ ' "

(b) I will jump to the bottom of this article, which states, "The woman started on the medication right away. It was called albuterol, a drug that has been used for decades to treat asthma. Among its many properties, albuterol can stabilize the neurotransmitter at that junction between nerve and muscle so that the command reliably gets through to the muscle."
(i) The albuterol is an adrenergic agonist, which means it acts on adrenergic receptor, like natural ligands epinephrine (also known as adrenaline) and norepinephrine produced in the body. An an adrenergic agonist will relax muscle in bronchioles, so as to dilate them (bronchioles).
(ii) However, its (albuterol's) mechanism to treat disorders in neuromuscular junction is unclear. See
(A) salbutamol
https://en.wikipedia.org/wiki/S
("also known as albuterol")

There is no need to read the rest of this Wiki page, except to peep at its chemical structure at the upper right corner.
(B) McMacken GM et al, Salbutamol Modifies the Neuromuscular Junction in a Mouse Model of ColQ Myasthenic Syndrome. Human Molecular Genetics (abbreviation: Hum Mol Genet) 28: 2339 (2019)
https://pubmed.ncbi.nlm.nih.gov/31220253/
("The β-adrenergic agonists salbutamol and ephedrine have proven to be effective as therapies for human disorders of the neuromuscular junction, in particular many subsets of congenital myasthenic syndromes. However, the mechanisms underlying this clinical benefit are unknown and improved understanding of the effect of adrenergic signalling on the neuromuscular junction is essential to facilitate the development of more targeted therapies")

The first author is British, which explains the spelling of "signalling."


(c)
(i) When an impulse from nerve reaches muscle, the nerve ending release acetylcholine.
(ii) acetylcholine
https://en.wikipedia.org/wiki/Acetylcholine
("it is an ester of acetic acid and choline")

View its chemical structure. That is all.
(iii) choline
https://en.wikipedia.org/wiki/Choline
("Choline is a quaternary ammonium cation"/ section 14 or the last section History: for name)

Usually a nitrogen atom forms three bonds and keep the nitrogen uncharged. But when the nitrogen forms four bonds (as in choline), the nitrogen atom is necessarily one plus in charge (because its reserved pair of electrons is used to form the fourth bond, the other partner of the fourth bond does not contribute an electron).
(iv) Once acetylcholine is released at neuromuscular junction, it will activate acetylcholine receptor(s) on the muscle (so that the muscle contracts). At the same tie the acetylcholinesterase split acetylcholine (to acetate and choline) to inactivate it (acetylcholine), so that the next wave of impulse may repeat the same cycle and muscle contract again.

(d) A picture is worth a thousand words.

Dvir H et al, Acetylcholinesterase: From 3D Structure to Function. Chemico-Biological Interactions (abbreviation: Chem Biol Interact) 187: 10 (2010)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2894301/
(i) Figure 2 shows that one acetylcholinesterase (AChE) has two sites: "ES, esteratic site; AS, anionic substrate binding site." The acetylcholine is guided into the gorge in AchE, by "14 conserved aromatic" amino acids. See Figure 4 and the sentence right before it ("conserved" means the same from lower life to humans).

The sentence immediately following Figure 1 said, "The various oligomeric forms of AChE in the electric organs of the electric fish, Electrophorus and Torpedo, are structurally similar to those in vertebrate nerve and muscle." And the figures in this review shows AChE from Topedo.
https://en.wikipedia.org/wiki/Common_torpedo
(ii) Figure 5 shows a dimer of AChE. Tc in front of AChE is the binominal name of Torpedo californica (not common torpedo but another species within the genus). The lower panel in Fig 5 is the same dimer but viewed "down the 2-fold axis."
(iii) Figure 6 shows a monomer, or just one, AChE. Take notice that a red cylinder is an alpha helix (formed by amino acids of course). You can see that alpha 9 (helix) in Fig 6 is near the -COOH, the one end of the AChE protein ("C terminus" where C comes from carboxyl group -COOJ). Return to the lower panel of Fig 5, you will see that one helix -- the helix you can look through the cire like a telescope -- from each of the AChE dimers (around the two-fold axis) has a short tail that ends. Those (two) are alpha 9's.

Figure 6 also shows a beta sheet of eight strands of amino acids (named beta 1 to 8). You can not see the sheet in Figure 5. The sheet has not biological function, but is there.
(iv) Figure 7 shows the side-view of the gorge at one AChE. Note the four aromatic amino acids represented by hexagons and (hexagons plus pentagons).
(v) After Figure 10 (which you need not view) is the statement: "The functional AChE species at vertebrate cholinergic synapses [or junctions] are formed by four AChET [T in the original text is a subscript, which you need not know] subunits [forming a tetramers, rather than dimers; dimers was shown at Figure 5 to make it simple] associated with either the collagenous protein ColQ * * * This interaction [with ColQ] requires the highly conserved C-terminal T-sequence of AChET, which forms an amphipathic helix."

Go to Figure 11 and see the four C termini (plural of terminus) interact with the ColQ which is represented by a helix right in the middle, splits the figure into two halves: right and left. ColQ us a kind of collagen, which is made up of three strands (of amino acids; called triple helix, in contrast to double helix in DNA) forming helix throughout.

Fig 6 shows a tetramer of AChE (four AChE proteins) adheres to one ColQ (gray). The yellow patches (there are two: one in lower right on the magenta AChE protein, and the other in upper left on the navy blue AChE protein) are the active sites that hydrolyze acetylcholine. The other two active sites (because there are four AChEs) can not been seen from this perspective..   

(e) The end result of the assembly is demonstrated in Figure 1 of Campanari M-L et al, Neuromuscular Junction Impairment in Amyotrophic Lateral Sclerosis: Reassessing the Role of Acetylcholinesterase. Frontiers in Molecular Neuroscience (abbreviation: Front Mol Neurosci) 9: 160 (2016)
https://www.frontiersin.org/arti ... mol.2016.00160/full
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The 40-year-old woman glared at the windows in her Lower Manhattan apartment. They were filthy. She wanted to wash them. God knows they needed it. But she couldn’t. She considered what it would take to do the job. First, she would have to be on her feet for maybe 20 minutes. Impossible. After standing for more than a few minutes, her legs would tremble with fatigue. She might have the strength in her arms to clean the lower half of a window — maybe one or two of them — but the top? Forget it. On her best day, she could lift her arms up over her head, but she couldn’t keep them up. Her muscles tired too quickly. No, if she wanted clean windows, she would have to hire someone. The thought was depressing. But it was that frustration that eventually led her back to the office of Dr. Mary Lynn Chu.

Chu is the medical director of the pediatric Muscular Dystrophy Association care center at N.Y.U. Langone Orthopedic Hospital. She had been the woman’s doctor, off and on, since she was a tween, a few years after getting the diagnosis of limb-girdle muscular dystrophy (L.G.M.D.). These are inherited disorders of the muscles that power the arms and legs. Patients with one of the many versions of the disease often have trouble walking or standing up from a chair. Lifting objects or even brushing their hair or teeth may be difficult and eventually impossible. Many, like this woman, need to use a wheelchair to get around.

From the time this patient first learned to walk, she was clumsy. She fell frequently, and going up stairs was a nightmare. Long after the age when other children ran up the stairs effortlessly, she would struggle, using her arms to pull herself up by the banisters.

Her mother tried to help her with her balance and strength by enrolling her in ballet. It was so awful that the girl quit after a single class. She tried taekwondo and tap dancing — but none of these activities helped at all. It soon became clear that this wasn’t just clumsiness. And that recognition marked the start of her medical odyssey. Her parents took her to doctor after doctor in New York City before one specialist finally put a name to it: limb-girdle muscular dystrophy. There was no cure for this disorder, and no effective treatment, save for those to relieve the pain that can accompany the disease. Physical therapy is used to help preserve strength, but the disease is progressive — sometimes slowly, sometimes more rapidly. When she was 6, the girl had a biopsy of her muscle to identify which type of limb-girdle disorder she had. It was inconclusive. Still, her doctors agreed that L.G.M.D. was the most likely diagnosis.

The patient liked Chu from the first visit. She was only 12, but she felt that this doctor took her seriously and didn’t treat her like a child. Still, whenever she saw Chu, the doctor was surrounded by medical students and other trainees. They would stand and watch as Chu put her through an exam that she soon knew by heart. First Chu would ask her to raise her arms straight out from her shoulders, like an airplane, and then keep them up as the doctor — or one of the trainees — would push down. It was like a contest, one that she never won. And then there were all the things they asked her to do that she simply couldn’t. She couldn’t walk on her tiptoes; couldn’t walk with her feet heel to toe like a tightrope walker — at least not without falling.

Chu encouraged the girl to see a genetics counselor. This was an inherited disease, she argued, and they were the experts on inherited diseases. The right test could provide a definitive diagnosis. But the patient didn’t see the point — what did it matter which form of the disease she had if there was no treatment? She didn’t want to go, and her mother wouldn’t make her. She saw Chu every six months for years, but when she was ready to start college, she decided she needed a break. It wasn’t as if they could do anything for her, that was clear.

Givng Genetic Testing a Try
Over the next decade her visits to Chu became less regular. Her disease seemed stable. It’s true she wasn’t getting better, but at least she wasn’t getting any worse. But at 34 she decided to focus once more on her disease. Chu persuaded her — and her equally reluctant insurance company — to get a genetic test. This test looked for 13 genes that are linked to L.G.M.D. She had already been through a veritable alphabet of testing, none of which had confirmed a specific diagnosis. But when the phone call came, the news was still devastating: The test was negative for the genes associated with L.G.M.D.

But Chu didn’t give up. Two years later, the Muscular Dystrophy Association arranged for free genetic testing for patients who, like her, did not have a definitive diagnosis. This time they would look at 35 newly identified limb-girdle-weakness-related genes. But when this test, too, came back uninformative, she made a decision: She wasn’t going to be tested again. It was just too emotionally difficult.

But that fall day when she was unable to imagine washing her windows, she went back to Chu. Chu sent the patient to see Dr. John Pappas, the head of clinical genetics at the N.Y.U. Langone pediatrics department. Pappas was a big man with a warm presence and a melodic Greek accent. After hearing the patient’s story, he agreed that genetic testing would be useful, but as she had already been screened twice without answers, he proposed that she have all the active components in her DNA — the parts called exomes — tested. Looking more broadly might very well give them an answer. The results would take months to come back, Pappas warned. The woman tried not to get too hopeful. Two months passed. Then three. Would this be yet another soul-crushing disappointment?

Three Months of Waiting
It was nearly 8 p.m. and the patient was working late at her job when her cellphone rang. She glanced down and her heart began to race. It was the N.Y.U. genetics division. “I have some good news,” Pappas said when she answered. They had a diagnosis for her. She had something known as congenital myasthenic syndrome (C.M.S.). As with the muscular dystrophies, there are many varieties of C.M.S. Hers was caused by an abnormality in a gene called COLQ. “And the best news,” he said: “There is a treatment.”

At that moment, the woman felt her whole world shift. It had been so long. She began to sob.

In C.M.S., the weakness and early fatigue is caused by a problem at the link where the nerves that carry the brain’s command connect to the targeted muscle. Instructions to the muscle prompt the release of a neurotransmitter — a compound whose job it is to carry the information between the nerve and the muscle. When the COLQ gene doesn’t work properly, the junction between nerve and muscle gets flooded with the neurotransmitter, and the whole system breaks down. The patient feels the muscle quickly tire, its strength dwindle.

The woman started on the medication right away. It was called albuterol, a drug that has been used for decades to treat asthma. Among its many properties, albuterol can stabilize the neurotransmitter at that junction between nerve and muscle so that the command reliably gets through to the muscle.

She felt the difference immediately. Her muscles still fatigued, but for the first time in her life she could feel herself getting stronger. She had used a wheelchair since she was 12 because she couldn’t walk more than a few steps without terrible fatigue. With this medication she felt that every day she could walk a little farther and do a little more.

Proof came quickly. A couple of months later, the patient noticed she had left her book on the balcony. Rain had started. She was in her socks and walked over the wet balcony floor to grab the book. She looked down and realized that she was on her tiptoes. She hadn’t been able to tiptoe for decades. She was ecstatic. She walked on her tiptoes throughout her small apartment. More than ever before she could see a normal life stretching out before her.

It has been five years, and that dream has been realized. Just a few months ago, the elevator in her apartment building broke. In the past she might have just gone to her parents’ apartment and stayed there until it was fixed. After all, she lived on the 11th floor. But that day she thought: No. And she climbed the stairs all the way to her apartment. She didn’t even have to stop. Not once.

And she is now able to wash her own windows.

Lisa Sanders, M.D., is a contributing writer for the magazine. Her latest book is “Diagnosis: Solving the Most Baffling Medical Mysteries.” If you have a solved case to share, write to her at Lisa.Sandersmdnyt@gmail.com. More about Lisa Sanders, M.D.