MIM – P2, P3, P4 Variants

MIM (Muscle Integrithy Myopathy), also known as PSSM2 (Polysacharide Storage Myopathy Type 2), is a term connected to myopathic episodes in horses. As we described in our previous article about MIM, unlike PSSM1 (Polysacharide Storage Myopathy Type 1) and other muscle diseases such as MYHM (Myosin-Heavy Chain Myopathy) or HYPP (Hyperkalemic Periodic Paralysis), no link has been found between genetic markers and the clinical manifestation of MIM. The final diagnosis should therefore be based on clinical symptoms, muscle biopsy, and ruling out other possible causes.

Symptoms of MIM include reluctance to go forward, decline in performance, reluctance to collect, difficult canter transition/leads, generalized atrophy, intermittent lameness, muscle fasciculations, poor topline, difficulty backing up, bucking, sensitivity to grooming, and rhabdomyolysis.

Regarding MIM, you may have come across six different variants – P2, P3, P4, P8, Px, and K1. In this article, we‘ll look more into the first three mentioned, and we will cover the other three in another article coming out in a few weeks. It’s important to note that none of these variants has been associated with clinical disease in peer-reviewed scientific publications as of today.

• The P2 variant is linked to the MYOT gene, which encodes myotilin, a protein localised in Z-discs of muscle sarcomeres. The mutation was found in multiple breeds, including warmbloods and Arabians, and even in the Przewalski horses, which are not direct ancestors of modern horses. This suggests that the P2 variant is at least over 35 000 years old. It should be mentioned that mutations with a notable negative effect on their carriers usually do not persist in the species‘ population over such a long period of time.  In humans, mutations in the MYOT gene have been linked with MFM (Myofibrillar myopathies).

• The P3 variant is mentioned in relation to the FLNC gene (Filamin C), which encodes a protein that connects the Z-discs and muscle (actin) filaments. Two P3 variants have been described – the P3a variant, which is predicted to cause a substitution of glutamic acid with lysine in the protein, and the P3b variant, causing the substitution of alanine with threonine. Studies (1, 2) report no difference in allele frequency between the affected and control groups. In humans, mutations in the FLNC gene also seem to cause MFM.

• The P4 variant is predicted to cause changes in the MYOZ3 gene (Myozenin 3), which is one of the proteins forming the Z-discs. As in the previous cases, it has been found in multiple breeds, and the difference between the affected horses and control groups has not been found statistically significant.

Stay around, we’ll look into the other three remaining variants (P8, Px, K1) soon!