Fins, fur, and wings: the study of Tmem161b across species, and what it tells us about its function in the heart

Abstract

Transmembrane protein 161b (Tmem161b) was recently identified in multiple high-through-put phenotypic screens, including in fly, zebrafish, and mouse. In zebrafish, Tmem161b was identified as an essential regulator of cardiac rhythm. In mouse, Tmem161b shows conserved function in regulating cardiac rhythm but has also been shown to impact cardiac morphology. Homozygous or heterozygous missense mutations have also recently been reported for TMEM161B in patients with structural brain malformations, although its significance in the human heart remains to be determined. Across the three model organisms studied to date (fly, fish, and mouse), Tmem161b loss of function is implicated in intracellular calcium ion handling, which may explain the diverse phenotypes observed. This review summarises the current knowledge of this conserved and functionally essential protein in the context of cardiac biology.

Fig. 1

Summary of cardiac phenotypes observed in wildtype and TMEM161B knockout (KO) mouse embryos. At 14.5 dpc, TMEM161B KO embryos have VSDs and atrial and ventricular defects (AVSD, cyan asterisks). At 17.5 dpc, TMEM161B KO embryo hearts have altered morphology (although no reported VSD or AVSD), with thickened interventricular septum (cyan scale bar) and increased cell number. Isolated cardiomyocytes exhibit altered Ca.²⁺ oscillation, compared with wildtype littermates. At 18.5 dpc, the ventricular walls of TMEM161B KO embryonic hearts are considerable thicker (cyan scale bars) and, in some instances, almost entirely occlude the chamber lumen. Phenotypic summary derived from published data (Koopman et al. ; Spielmann et al. 2022) and IMPC data (http://www.mousephenotype.org/data/embryo)