Tmem94-KO Mouse

TMEM94, also known as ERMA, is a protein-coding gene. Conventional and AlphaFold2 predictions suggest it has characteristics analogous to P-type ATPases, uniquely combining a P-type ATPase domain and a GMN motif. It functions as a transporter for Mg2+ uptake in the endoplasmic reticulum, which is crucial for maintaining intracellular Mg2+ homeostasis [1]. Mutations in TMEM94 are associated with various disorders such as intellectual developmental disorder with cardiac defects and dysmorphic facies (IDDCDF) [2].

Loss-of-function experiments have provided insights into its role. In mouse models, loss of Tmem94 generated by CRISPR/Cas9 was embryonic lethal and led to craniofacial and cardiac abnormalities and abnormal neuronal migration pattern, indicating its importance in craniofacial, cardiovascular, and nervous system development [4]. Decreased expression of TMEM94 in human iPSC-cardiomyocytes and mouse Erma+/- cardiomyocytes led to cardiac dysfunction and abnormal Ca2+ cycling, highlighting its role in cardiac function [1]. In pancreatic cancer cells, decreased TMEM94 expression inhibited cell proliferation and migration [3].

In conclusion, TMEM94 is essential for Mg2+ uptake in the endoplasmic reticulum and plays a crucial role in the development of craniofacial, cardiovascular, and nervous systems. Its loss-of-function in animal models has revealed its significance in these biological processes and its association with diseases like IDDCDF and pancreatic cancer, which may help in understanding disease mechanisms and developing potential therapeutic strategies.

References:

1. Vishnu, Neelanjan, Venkatesan, Manigandan, Madaris, Travis R, Stathopulos, Peter B, Madesh, Muniswamy. 2024. ERMA (TMEM94) is a P-type ATPase transporter for Mg2+ uptake in the endoplasmic reticulum. In Molecular cell, 84, 1321-1337.e11. doi:10.1016/j.molcel.2024.02.033. https://pubmed.ncbi.nlm.nih.gov/38513662/

2. Al-Hamed, Mohamed H, Alsahan, Nada, Tulbah, Maha, Sayer, John A, Imtiaz, Faiqa. 2020. Fetal Anomalies Associated with Novel Pathogenic Variants in TMEM94. In Genes, 11, . doi:10.3390/genes11090967. https://pubmed.ncbi.nlm.nih.gov/32825426/

3. Zhou, Yuan, Huang, Borong, Zhang, Qinqin, Yu, Yaqun, Xiao, Juan. 2024. Modeling of new markers for the diagnosis and prognosis of pancreatic cancer based on the transition from inflammation to cancer. In Translational cancer research, 13, 1425-1442. doi:10.21037/tcr-23-1365. https://pubmed.ncbi.nlm.nih.gov/38617519/

4. Stephen, Joshi, Maddirevula, Sateesh, Nampoothiri, Sheela, Gahl, William A, Malicdan, May Christine V. . Bi-allelic TMEM94 Truncating Variants Are Associated with Neurodevelopmental Delay, Congenital Heart Defects, and Distinct Facial Dysmorphism. In American journal of human genetics, 103, 948-967. doi:10.1016/j.ajhg.2018.11.001. https://pubmed.ncbi.nlm.nih.gov/30526868/