deficiency disrupts the centrosome-check point in the brain and causes primary microcephaly.

Microcephaly affects 1 in 2,500 babies per year. Primary microcephaly results from aberrant neurogenesis leading to a small brain at birth. This is due to altered patterns of proliferation and/or early differentiation of neurons. Premature differentiation of neurons is associated with defects in the centrosome and/or primary cilia. In this study, we report on the first patients identified with -deficiency and utilize a conditional mouse model to ascertain the molecular mechanisms associated with -deficient primary microcephaly. We identified homozygous variants in these patients who displayed profound primary microcephaly in addition to intrauterine growth restriction, cervical kyphosis, severe contractures of joints, and facial dysmorphia. We then generated a mouse model using to ablate from the forebrain. The mice presented with severe microcephaly starting at E18.5. Neurospheres generated from the forebrain of conditional deletion mice were used to support the pathogenicity of the patient variants. We show that loss of increases both canonical and non-canonical cell death, but that loss of fails to rescue microcephaly in the mouse model. Examination of neurogenesis in mice revealed distinct alterations in proliferation and cellular migration accompanied by supernumerary centrosomes and cilia. We therefore propose that is a novel primary microcephaly-related gene and that the role of in centrosome and cilia regulation is crucial for proper neurogenesis.