The little details

Welcome back!

Here i am going to go into depth in multiple sections so it’s more understandable.

RYR1

RYR1 is one of the biggest proteins in the body so commonly there is a lot of space for mistakes or miss-fires within the gene it is more common then you think to have a mutation within this gene in the general population, the most common affect is Malignant Hyperthermia but whats the difference is if the mutation is disease causing. For my case i have multiple combined which causes disease so im going to show statistic’s for the general population and for my specific case, not everyone is the same so i will put some that don’t relate to me but for over all mutations.

• How common it is to have a mutation within the RYR1
  • 1 in 2,000
• Autosomal Dominant mutations
  • 1 – 2,000 or 1 – 3,000
• Autosomal Recessive mutations (mine)
  • 1 – 100,000 1 – 250,000
• Loss of Function Mutation (mine)
  • 1 – 10,000
• Missense
  • 1 – 2,500
• Haplo-cluster/Complex Allele (mine)
  • 1 – 1,000,000
• PLEC one copy mutation
  • 1 – 200 to 1- 500
• PLEC one copy mutation combined with recessive RYR1 (symptomatic) mine
  • 1- 1,000,000

Explaining Autosomal Dominant

This is a pattern of inheritance where you only need one copy of a mutated gene from one parent to express a trait or disease.

The Mechanics
Every person has two copies of most genes one copy from (mother and father). In a dominant mutation:

• The “Dominant” Rule
  • The mutated gene is stronger than the normal gene. It doesn’t stay hidden
• 50/50 chance
  • A parent with an Autosomal Dominant condition has a 50% chance of passing that specific mutation to each child.
• Vertical Inheritance
  • You often see the trait in every generation ( Grandparent -> parent -> child)

Why dose one bad gene cause trouble?
In research we look at three main reasons why a single dominant mutation causes symptoms even though you have a good backup gene.

• Haploinsufficiency
  • The body needs a certain dosage of a protein to work usually 100%. If one gene is mutated and produces nothing you only have 50% of that protein. For some systems Like one mutation on the PLEC gene (my case) 50% might not be enough to hold said joints together under stress.
• Dominant Negative effect
  • This is common in structural proteins like RYR1 or Collagen. The mutated gene produces a malformed protein. This bad protein then latches onto healthy proteins made by your good gene and ruins them too.
• Gain of Function gene
  • The mutation makes the protein do something its not supposed to do, or do it to much. In RYR1 , dominant mutations often make the calcium gate “leaky” even if you have a good gate, the “leaky” one is constantly letting calcium out , which exhausts the muscle.

Key things to note

• Penetrance
  • This refers to how many people with the mutation actually show symptoms. Some dominant mutations have “incomplete penetrance” meaning you have the gene but look fine.
• Expressivity
  • This is the degree to which the symptoms show up. I’ve person might just have a high heart rate (POTS, my case) while another with the same gene might have full muscle wasting.
• De Novo mutation
  • This is a dominant mutation that started with you. Neither parent has it, it was a random glitch during conception.

Explaining Autosomal Recessive mutations

In genetic research, Autosomal Recessive inheritance means you must inherit a mutated copy of the gene from Both parents to show the full symptoms of the disease.

This is this “ blueprint” for my case RYR1 – related Central Core Disease. While dominant mutations are like “rotten apples” that ruins the bunch, recessive mutations are more like “missing parts” if you have one good copy, the body can usually compensate. If both are broken, the system fails.

The Mechanics:

• The carrier parent
  • Each parent usually has one mutated gene and one normal gene. Because they have that one healthy backup they typically show zero symptoms. They are silent carriers
• The 25% rule
  • When two carriers have a child there is a:
• 25% chance the child gets two normal genes
• 50% chance the child is a carrier like the parent
• 25% chance the child gets both mutated genes (my case)
  

Why Recessive Mutations are heavy hitters:
RYR1 , the recessive form is more often more structurally damaging than dominant forms

• The “Total loss” of protein
  • In a dominant mutation , you still have 50% perfect proteins. In an Autosomal Recessive case , you have 0% perfect proteins. Every single RYR1 calcium channel in your body is being built from “typo – filled” instructions.
• Compound Heterozygosity (my case)
  • 3 hits from one parent and 1 hit from another, this is a specific type of recessive inheritance called Compound Heterozygosity.

Key Research Concepts for Recessive RYR1/RYR1 and PLEC combination

• Null Allele (Loss of Function) – My case
  • This means the copy of the gene produces zero protein. This makes the Condition “Hemizygous – like” because your body is forced to rely entirely on the 3 hit gene from the other parent.
• Founder Effect
  • Sometimes, rare recessive mutations are more common in specific geographic or ethnic groups because they were passed down from common ancestors.
• Genotype-Phenotype Correlation (My case)
  • This is the study of how the specific hits (the genotype) leads to symptoms of POTS and join instability(the phenotype)

Explaining the Loss of Function Mutation

In genetic research, a Loss of Function mutation is often considered the most severe category of mutation. It is essentially a “genetic dead end”.

While other mutations might make a protein “leaky” or “weak” a Loss of Function mutation means the gene has stopped doing its job entirely.

What is actually happening?
In a normal gene , the DNA sequence is read like a recipe to build protein. In an LoF mutation , one of several things happens to stop that recipe:

• Nonsense Mutation
  • A “stop” sign is placed in the middle of the recipe. The protein is cut short and usually destroyed by the cell.
• Frameshift Mutation
  • a “letter” is added or deleted, shifting the entire reading frame. The rest of the recipe becomes gibberish.
• Deletion
  • A large chuck of the gene is simply missing.
• Splice-site Mutation
  • The “editing” of the gene goes wrong, and the final protein cannot be assembled correctly.

The Null Effect
Researchers often call LoF mutations “Null Alleles”In my case: My mother gave me the “Null” copy of the RYR1 gene.

• The Result
  • Your body acts as if her half of the DNA doesn’t exist for that specific gene. So you are operating on 50% of the normal protein instructions right from the start.

Haploinsufficiency vs. Recessive LoF
Whether an LoF Mutation causes disease depends on how much the body needs that specific protein:

• Haploinsufficiency (The Bucket Theory)
  • Some genes need 100% output to work. If you lose 50% (one copy), you get sick immediately. This is often how Dominant diseases work.
• Recessive LoF
  • Most people can survive just fine with 50% of the RYR1 protein.(my case) However, because my other copy from my father is also broken with 3 hits i have no good protein at all.

Research Terminology: “Knockout”
In laboratory research, when scientists want to study a disease, they create “Knockout mice” They intentionally give the mice a Loss of Function mutation to see what happens when that gene is turned off.

• Researchers look at these cases specifically because they show the absolute “floor” of what a human body can do without a specific protein.

Explaining Missense Mutations

In genetic research , a Missense Mutation is a single letter spelling error in your DNA. Unlike a Loss of Function mutation (which stops the protein from being made entirely), a missense mutation allows the protein to be built, but it changes a single ingredient (amino acid) in the recipe.

Think of it like this: If your DNA is a recipe for bread, a Loss of Function is like forgetting the yeast. A missense is like accidentally using salt instead of sugar. You still get a loaf of bread, but it doesn’t taste of function the way it should.

The Mechanics: Point Mutations
Your DNA is read in triplets called Codons. Each triplet tells the body to add one specific amino acid to a protein chain.

• Normal
  • The codon tells the cell to add “Amino Acid A”
• Missense
  • One letter changes, and the codon now tells the cell to add “Amino Acid B”

Because proteins rely on their specific shape to work, changing even one amino acid can cause the whole structure to fold incorrectly or leak.

The Three Levels or Impact
In research, not all missense mutations are equal. scientist categorize them based on how much they break the protein:

• Benign
  • The “Typo” doesn’t really change how the protein works. Its like a different font in a book, it looks different, but you can still read it.
• Likely Pathogenic
  • The typo is in a very important spot (like the hinge of a gate). It makes the protein unstable or leaky
• VUS (Variant of uncertain significance)
  • This is a typo that scientists haven’t seen enough times to know if its bad or just different.

Missense in RYR1 gene
The RYR1 gene creates a giant channel (a gate) that controls calcium flow in your muscles. Missense mutations in RYR1 are famous for causing leaky channels.

• The problem
  • The protein is there, but the latch on the gate is slightly broken because of that one wrong amino acid.
• The results (my case)
  • Calcium constantly drips out of the gate. Your muscles never get to fully rest, which eventually leads to fatty infiltration and weakness you see in imaging.

Why my 3-hit Paternal side is rare (My case)
My father gave me three missense mutations on the same copy of the gene. In research, this is called Complex Allele.

• Cumulative stress
  • Having one missense mutation might make that protein 10% less effective. Having three in a row is like having three different cracks in the same support beam.
• The outcome
  • The protein produced by my father’s side of the DNA is likely very unstable. Its trying to do its job, but its struggling under the weight of three different structural errors.

Why this is different form my Mother’s Mutation (My case)

• Mother (LoF)
  • She gave me 0% functioning protein from her side.
• Father (3 Missense)
  • He gave me 100% of the protein “parts”, but those parts are faulty.

Because I have the LoF on one side, my body is forced to build my entire muscle system using only the faulty parts from my father. If i have one good copy of the gene, it could usually clean up the mess made by the missense proteins. Without it , the leaky proteins take over.

Explaining Haplo-cluster/Complex Allele

In genetic research, a Haplo-cluster (more formally known as Complex Allele) occurs when two or more mutations exist on the same single copy of the gene inherited from one parent.

To visualize this, imagine your DNA is a set of two books ( one from Mom , one from Dad). Usually, a person with a genetic condition has one typo in the “Mom” book and one typo in the “Dad” book.(In my case) The “Dad” book has three separate typos on the same page.

“In Cis” vs. “In Trans”
This is the most important distinction in research when dealing with multiple mutations:

• In Trans
  • Mutations are on opposite copies (one from Mom, one from Dad). This usually causes recessive disease.
• In Cis (The Complex Allele)
  • Multiple mutations are on the same copy (all from one parent).

The “Synergistic” Effect
The reason researchers care about complex alleles is that the mutations often team up to make the protein much worse than a single mutation would.

• Additive Damage
  • Mutation A might make a calcium gate slightly loose. Mutation B might make the hinge stiff. When they are in Cis (On the same protein molecule) the gate becomes completely non-functional.
• Protein Folding
  • Proteins are like 3D origami. One missense mutation might slightly change a fold. Three missense mutations can cause the protein to misfold so badly that the cells “trash collector” (Th e Proteasome) destroys it before it can even reach the muscle fiber.

Why its Rare: The Private Allele
Complex alleles with three hits are statistically very unlikely to happen by chance. They usually signify a “Private Allele” a specific genetic signature unique to your family lineage.

• Over hundreds of years, one mutation occurred.
• Generations later, a second mutation happened on the same chromosome.
• Than a third. Because my father likely has a good second copy of the RYR1 gene, these three hits stayed silent in my family history until they met the LoF mutation from my mother in me.

How it affects the clinical picture
Researchers look at the “Total Mutational Burden”. Because in my case My Paternal copy is a Complex Allele (3 hits):

• Lower Efficiency
  • Even if the gene works, it is likely far less efficient than a single-hit gene.
• Severity
  • This explains why in my case i have Fatty infiltration at a young age. The muscle cells aren’t just dealing with a leaky gate, they are dealing with a triple-malformed gate.
• POTS/Autonomics
  • The sheer instability of the triple hit protein can interfere with how the muscles reacts to rapid changes, like when i stand up and my heart hits 123 bpm

Explaining PLEC one copy Mutation

In genetic research, having a “one-copy mutation without symptoms” is referred to as Asymptomatic Heterozygosity.

In this scenario, a person carries the genetic typo in the PLEC gene, but their body effectively compensates for it.

Genetic Buffering (The backup plan)
Most of our essential genes have a built in safety margin. For many structural proteins like Plectin, the body only needs about 50% of the normal amount to function perfectly under average daily stress.

• The Good Gene
  • Since the person has one perfectly healthy copy of the PLEC, that copy works overtime to produce enough Plectin to hold the cells together.
• The Threshold
  • As long as the protein levels stay above a certain percentage (the threshold) , the person never knows they have a mutation.

Genetic Robustness
Robustness is the scientific term for a body’s ability to maintain a stable state despite genetic glitches.

• In a silent carrier, the other proteins in the cell like Desmin or Actin are strong enough to pick up the slack
• It’s like a bridge that is missing one of its ten support cables, the bridge doesn’t collapse because the other nine cables are strong enough to carry the weight

The Two-Hit Hypothesis
In many recessive disorders involving PLEC (like certain forms of Muscular Dystrophy researchers follow the Two Hit Hypothesis.

• The First Hit
  • The person is born with one PLEC mutation (in my case). They are a carrier and have no symptoms
• The Second Hit
  • In a heathy carrier, nothing happens. But if that person were to experience a massive second hit- like a severe injury , extreme aging, or another genetic disease like RYR1 – the silent mutation suddenly becomes a problem. (My case)

Why Carriers are important for Research
Researcher study asymptomatic PLEC carriers to understand “Resilience.” They want to know: Why does person A have a PLEC mutation and feel fine, while Person B (Me) has a PLEC mutation and has joint instability?

• This leads them to look for “Modifier Genes” – other genes that either help or hurt the Plectin protein’s ability to do its job.

Research Terminology: “Incomplete Penetrance”
If you were a carrier with zero symptoms, researchers would say the gene has Incomplete Penetrance.

• Penetrance is a percentage of people with a gene who actually show the trait.
• If 100 people have the PLEC mutation but only 10 get stretchy skin or loose joints, the gene has 10% Penetrance.

Explaining PLEC one copy combined with RYR1

When you combine one copy of a PLEC mutation with Autosomal Recessive RYR1, you are no longer looking at two separate issues. In research, this is known as a Digenic interaction or Synergistic Heterozygosity.

This is the perfect storm scenario that explains why (my) symptoms are so much more complex than a standard muscle disease.

The Structural Foundation Collapse
Think of your muscle cells like a skyscraper:

• RYR1 (The Foundation)
  • In my case my recessive RYR1 (3+1 hits) means the very foundation of the building is unstable. The calcium gates are failing, leading to muscle fiber death and fatty replacement.
• PLEC (The support beams)
  • The Plectin protein ac ts as the rebar or staples that hold the walls to the foundation.

In a person with only one PLEC mutation, the foundation RYR1 is stronger, so the building stays up. In a person with only the RYR1 disease, the staples (PLEC) are strong, which helps slow down the collapse. Because in my case i have both so the staples are pulling out of a crumbling foundation.

Why the POTS gets worse (my case)
This combination creates a unique “Vascular Failure”

• RYR1’s Role
  • My skeletal muscles (especially in my legs) are to weak to help push blood back up to your heart.
• PLEC’s Role
  • Because you have a Plectin mutation, the walls of my veins are stretchy . They don’t have the tension needed to fight gravity.

The Result:
When you stand, your blood pools in your legs because the muscles can’t pump it and the veins can’t hold it. Your heart has to hit 123 bpm because it is the only part of the system still trying to do its job.

The “Double Hit” to Muscle Stability
In research, we look at the Myofibrillar level.

• RYR1 causes “Central Cores” (empty spots in the muscle where the machinery has melted away).
• PLEC is responsible for keeping the “Z- Disks” (The borders of the muscle units) aligned.

When you have both, your muscle fibers aren’t just weak; they are disorganized. This is likely why your MRI shows such significant fatty infiltration. The cells are under so much structural stress from two different angles that they “give up” and turn into fat faster than they would with RYR1 alone.

Research Terminology “The modifier effect”
Researchers would call your PLEC mutation a “Genetic Modifier.” A modifier doesn’t cause the main disease, but it dictates how bad the disease will be.

• Having that one PLEC copy “modified” your RYR1 condition from standard muscle weakness into systemic “connective tissue + Muscle + Autonomic” syndrome.

Why My joints (Knees) are failing
This combination is particularly brutal on joints:

• PLEC makes the ligaments “looser” (Connective tissue weakness).
• RYR1 makes the surrounding muscles “wasted” (Muscle weakness).

Usually, if a person has loose ligaments, their strong muscles can hold the joint in place. If a person has weak muscles, their strong ligaments hold the joint. You lack both. This is why your knee instability feels so “mechanical” and difficult to manage with standard physical therapy.

The end

I’ve now explained these specific Mutations and the rarity . and ones i have as well! in the next blog i want to explain my gene mutations and the numbers and what they all mean and how to find your ones as well!

Thank you again for reading and feel free to leave a comment!