Researchers Use ATPase Enzyme Assay to Study SMCHD1 Mutations

An ATPase enzyme assay – for more than just HTS. Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) is an important protein that plays a role in gene regulation through altering DNA by addition of methyl groups.  It also contributes to the normal development of the nose, eyes, and other structures of the head and face which subsequently leads to its role in disorders such as Bosma arhinia microphthalmia syndrome (BAMS) and Facioscapulohumeral muscular dystrophy type 2 (FSHD2). Whereas the hallmark sign of BAMS is the absence of an external nose, FSHD2 is a disease where muscle dystrophy is the leading symptom. These disorders vary in phenotype, but it has been known for years that SMCHD1 mutations are a contributing factor. A recent study found that mutations in the ATPase region, specifically, play an essential role.³

Since SMCHD1 has been shown to play a role in two disorders, obviously researchers are excited to find therapeutic possibilities targeting it. Specifically, Gurzau et al. looked further into mutations in the ATPase domain to determine the effects on both, the BAMS and FSHD2 disorders. Interestingly, using multiple methods including a Transcreener enzyme assay which measures the end point of ADP, the group found a loss of function (loss of ATPase activity) in SMCHD1 concerning  FSHD2, while observing a gain of function for patients with BAMS.⁴ Furthermore, these findings indicate mutations in the ATPase region of SMCHD1 are most likely affecting ATP binding and hydrolysis.⁴

Although the unique opposing effect on each of the disorders could lead to challenges in finding therapeutic strategies, more work is needed to gain more in-depth knowledge in regards to functionality and possible therapy.

More about the ATPase Enzyme Assay

Research by Gurzau et al. was performed to determine ATPase activity in patients with FSHD2 and BAMS. As part of their work, the team used an immunoassay measuring ADP as an endpoint. Find out more specific details regarding the assay here. Briefly, the nature of an ATPase is the enzyme that catalyzes the reaction from ATP to ADP, a large macromolecular biological catalyst, forming ADP as a product which can be measured by using specific antibody labeled with a fluorophore. The ATPase assay confirmed a loss in catalytic function due to the mutations found in patients with FSHD2. Additionally, the gain of function theory for people with BAMS was supported using the same assay revealing the significance of how an ATPase enzyme assay can be used to study two completely different human abnormalities.

References

1. Conditions G. Genetics Home Reference Facioscapulohumeral muscular dystrophy. 1:1-7. https://ghr.nlm.nih.gov/condition/facioscapulohumeral-muscular-dystrophy
2. Conditions G. Genetics Home Reference Bosma arhinia microphthalmia syndrome. :1-6. https://ghr.nlm.nih.gov/condition/bosma-arhinia-microphthalmia-syndrome
3. Shaw ND, Hospital MG, Brand H, et al. SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. 2017;(January 2019). doi:10.1038/ng.3743. https://www.ncbi.nlm.nih.gov/pubmed/28067909
4. SMCHD1 ATPase domain mutations in disease † 1. 2018. doi:10.1074/jbc.RA118.003104. http://www.jbc.org/content/early/2018/05/10/jbc.RA118.003104.full.pdf