TMEM161B
encodes an evolutionarily conserved widely expressed novel 8-pass transmembrane protein of unknown function in human. Here we identify
TMEM161B
homozygous hypomorphic missense variants in our recessive polymicrogyria (PMG) cohort. Patients carrying
TMEM161B
mutations exhibit striking neocortical PMG and intellectual disability.
Tmem161b
knockout mice fail to develop midline hemispheric cleavage, whereas knock-in of patient mutations and patient-derived brain organoids show defects in apical cell polarity and radial glial scaffolding. We found that TMEM161B modulates actin filopodia, functioning upstream of the Rho-GTPase CDC42. Our data link
TMEM161B
with human PMG, likely regulating radial glia apical polarity during neocortical development.
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