Mutations in TP73 Cause Cortical Malformation Consistent with Lissencephaly

TP73 belongs to the TP53 family of transcription factors and has therefore been well studied in cancer research. Studies in mice, however, have revealed nononcogenic activities related to multiciliogenesis.

Utilizing whole-exome sequencing analysis in a cohort of individuals with mucociliary clearance disorder and cortical malformation, we identified homozygous loss-of-function variants in TP73 in seven individuals from five unrelated families.

All patients exhibit a chronic airway disease and cortical malformation consistent with lissencephaly. Lissencephaly “smooth brain” is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. All affected exhibit central muscular hypotonia and moderate to severe cognitive dysfunction. Furthermore, all affected suffer from a mucociliary clearance disorder with chronic infections of the upper and lower airways and neonatal respiratory distress. One affected died at the age of 2 months due to respiratory failure.

Utilizing nasal brush biopsy we obtained respiratory epithelial cells via nasal brush biopsy. Analyses via immunofluorescence, transmission electron microscopy and western blot analysis showed TP73 deficient respiratory epithelia are reduced in length and a severely reduced number of multiciliated cells consistent with a defect in cell differentiation.

Publication History

Article published online:
28 October 2021