Gain- and loss-of-function mutations cause perinatal lethality in mouse models of Birk-Barel syndrome

Birk-Barel syndrome (BBS), also known as KCNK9 imprinting syndrome, is a neurodevelopmental disorder caused by mutations in the maternally expressed paternally imprinted KCNK9 gene that encodes the TASK3 potassium channel. The first mutation identified in patients with BBS was a loss-of-function variant that reduces the potassium current mediated by TASK3. Subsequent studies have uncovered additional pathogenic variants, including gain-of-function mutations, that increase TASK3 activity. Here, we show that both mutations resulted in the expression of the hyperactive Task3M159I variant or the hypoactive Task3G236R variant, which caused early postnatal lethality in mice when maternally inherited, confirming the monogenic nature of BBS. These results indicate that the pathogenesis of BBS involves mechanisms other than alterations in channel activity. Consequently, the proposed therapeutic strategies, such as pharmacological modulation of the TASK3 channel function or epigenetic reactivation of the paternal KCNK9 allele, do not seem to be viable options. These findings also demonstrate that TASK3 knockout mice are not suitable models for studying KCNK9 imprinting syndrome or for developing therapies for affected patients. Therefore, there is an urgent need for animal models that allow conditional expression of BBS-associated mutations.