MKRN3 Interacts With Several Proteins Implicated in Puberty Timing but Does Not Influence GNRH1 Expression

Venkatram Yellapragada, Xiaonan Liu, Carina Lund, Johanna Känsäkoski, Kristiina Pulli, Sanna Vuoristo, Karolina Lundin, Timo Tuuri, Markku Varjosalo, Taneli Raivio
Frontiers in Endocrinology 2019, 10: 48
Paternally-inherited loss-of-function mutations in makorin ring finger protein 3 gene ( MKRN3 ) underlie central precocious puberty. To investigate the puberty-related mechanism(s) of MKRN3 in humans, we generated two distinct bi-allelic MKRN3 knock-out human pluripotent stem cell lines, Del 1 and Del 2, and differentiated them into GNRH1 -expressing neurons. Both Del 1 and Del 2 clones could be differentiated into neuronal progenitors and GNRH1 -expressing neurons, however, the relative expression of GNRH1 did not differ from wild type cells ( P = NS). Subsequently, we investigated stable and dynamic protein-protein interaction (PPI) partners of MKRN3 by stably expressing it in HEK cells followed by mass spectrometry analyses. We found 81 high-confidence novel protein interaction partners, which are implicated in cellular processes such as insulin signaling, RNA metabolism and cell-cell adhesion. Of the identified interactors, 20 have been previously implicated in puberty timing. In conclusion, our stem cell model for generation of GNRH1 -expressing neurons did not offer mechanistic insight for the role of MKRN3 in puberty initiation. The PPI data, however, indicate that MKRN3 may regulate puberty by interacting with other puberty-related proteins. Further studies are required to elucidate the possible mechanisms and outcomes of these interactions.

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