The P4 Variant Of MIM Explained

When a horse is tested for MIM (PSSM2) they can come back heterozygous (N/P4) or homozygous (P4/P4) but what exactly is P4?

What Is P4?

P4 is a variant of MFM (Myofibrillar myopathy)

What Is Myofibrillar Myopathy?

Myofibrillar Myopathy or MFM is part of a group of disorders known as muscular dystrophy. Muscular dystrophy is a progressive disease caused by abnormal/mutative genes that causes muscle weakness, and loss of muscle mass.

What Does The P4 Variant Affect?

The P4 variant affects something called Myozenin 3

What Is Myozenin?

Myozenin 3 is a structural protein that’s encoded as the MYOZ gene, it is present in cardiac and slow twitch skeletal muscle; Myozenin also plays a vital role in Calcineurin signalling.

What Is The Function Of Myozenin?

Myozenin 3 works with Filamin-C, (what is affected in P3) and Myotilin (What is affected in P2) by binding muscle cells that are involved in linking Z disc like proteins in both cardiac and slow twitch skeletal muscle- so like cement it helps keeps everything in place. But this is not the only function of Myozenin; Myozenin also signals to something called Calcineurin; Calcineurin is a protein that is Calcium and Phosphatase dependent, Calcineurin activates T cells in the immune system; T cells play the critical role of immune response; T cells also kill off infected host cells that are carrying illness or infection, without T cells responding the immune system would be compromised or weakened. Myozenin signals to Calcineurin like a 999 call, which then alerts T cells like a siren, kicking them into action to fight off the bad guys!

The P4 Variant Of PSSM2 Explained
A T Cell; T cells are critical to the immune system by issuing immune response and fighting off infected host cells

What Happens When There Is A Gene Mutation In Myozenin 3?

When a genetic mutation occurs in Myozenin 3 the mutated Myozenin clusters together causing clumps also known as aggregates, these clumps prevent the proteins in muscles functioning normally, because Myozenin also plays a role in Calcineurin signalling this also means that immune response to illness or infection will be slowed and thus compromised, because of the multi-function of Myozenin it makes P4 one of the more difficult variants to manage.

How Does Having A Mutation In Myozenin 3 Cause A Horse To Be Symptomatic?

Lets look at this in an easy way- having mutations in Myozenin 3 is like building a house with no cement; you can still build it but at some point in time the house will crumple and fall to the ground. This is what happens in MIM horses, the mutation in that one gene affects the rest of the muscle structure, it might work for a little while but it is weakened, and as MIM is degenerative as time goes on more clumps occur and the muscle structure will become weaker, and weaker, leading a horse to eventually become symptomatic.

Why Are Horses Affected By P4 At Different Ages?

Because every horses body is different. Some horses bodies are stronger, some horses bodies are weaker, some horses are immature, while others are more mature, some horses are able to withstand pain and even grow accustomed to it, and some horses simply cant take the slightest ounce of pain and will let you know that something is wrong- Every single horse is an individual and different just like us!

Our Case Study On P4 Horses

In a large survey we are still conducting of all MIM variants we have 200 surveys. Of these 200, 21 of those horses where either Heterozygous or Homozygous for the P4 variant and here is what we found:

  • Breeds affected by the P4 variant in our survey were all Arabians, American Quarter Horses, American Paint Horses, Appaloosas, Appendix Quarter Horses, Warmbloods, and Welshes.
  • Affected horses ranged from 2-13 years old, the most common ages for P4 to strike were 4 and 8 years old.
  • 20 horses were Heterozygous for P4 (n/p4) while 1 horse was Homozygous for P4 (P4/P4)
  • The most common symptoms of P4 were Canter issues, Explosive behaviour, Tight muscles, and Lameness with 15 out of 21 horses displaying these 4 symptoms.

Other symptoms displayed by horses included:
Aggression/ Ataxia/ Bit Gnashing/ Camping out (standing out to pee but not going)/ Colic or Laminitis like symptoms/ Contact Issues/ Dark or bloody urine/ Depression/ Dragging toes/ Exercise intolerance/ Lethargy or laziness/ Losing topline/ Muscle Knots/ Muscle spasms/ Planting under saddle/ Reluctance to be saddled/ Rope walking/ Sensitivity/ Stiffness/Struggling with walking up and down hills/ Stumbling/ Sweating Profusely and breathing heavily/ Tying up or Azoturia

For more information on the P4 variant of MIM check out our YouTube video by clicking this link