Primate-specific ZNF808 is essential for pancreatic development in humans

Elisa De Franco; Nick D. L. Owens; Hossam Montaser; Matthew Neil Wakeling; Jonna Saarimäki‐Vire; Athina Triantou; Hazem Ibrahim; Diego Balboa; Richard C. Caswell; Rachel E. Jennings; Jouni Kvist; Matthew B. Johnson; Sachin Muralidharan; Sian Ellard; Caroline Fiona Wright; Sateesh Maddirevula; Fowzan Sami Alkuraya; Wafaa Nabil Laimon; Samar Sabir Hassan; Mohamed Ahmed Abdullah; Anders Fritzberg; Emma L. Wakeling; Nisha Nathwani; Nancy Samir Elbarbary; Amani Osman; Hessa Alkandari; Abeer Al-Tararwa; Abdelhadi M. Habeb; Abdulmoein Eid Al-Agha; Ihab Abdulhamed Ahmad

doi:10.1038/s41588-023-01565-x

Genetic & Genomic MedicineNature GeneticsNov 16, 2023

Peer-reviewed journal article

Primate-specific ZNF808 is essential for pancreatic development in humans

Elisa De Franco iD, Nick D. L. Owens iD, Hossam Montaser iD, Matthew Neil Wakeling iD, Jonna Saarimäki‐Vire iD, Athina Triantou iD, Hazem Ibrahim iD, Diego Balboa iD, Richard C. Caswell iD, Rachel E. Jennings iD, Jouni Kvist iD, Matthew B. Johnson iD, Sachin Muralidharan iD, Sian Ellard iD, Caroline Fiona Wright iD, Sateesh Maddirevula iD, Fowzan Sami Alkuraya iD, Wafaa Nabil Laimon iD, Samar Sabir Hassan iD, Mohamed Ahmed Abdullah iD, Anders Fritzberg, Emma L. Wakeling iD, Nisha Nathwani, Nancy Samir Elbarbary iD, Amani Osman, , Michaël Imbeault iD

PDF DOI Preprint

Post to X

Threads on X Post to Bluesky Threads on Bluesky

Abstract

Identifying genes linked to extreme phenotypes in humans has the potential to highlight new biological processes fundamental for human development. Here we report the identification of homozygous loss of function variants in the primate-specific gene ZNF808 as a cause of pancreatic agenesis. ZNF808 is a member of the KRAB zinc finger protein (KZFPs) family, a large and rapidly evolving group of epigenetic silencers that target transposable elements. We show that loss of ZNF808 in vitro results in aberrant activation of many transposable elements it normally represses during early pancreas development. This results in inappropriate specification of cell fate with induction of genes associated with liver endoderm and a loss of pancreatic identity. We show that ZNF808 and its transposable element targets play a critical role in cell fate specification during human pancreatic development. This is the first report of loss of a primate-specific gene causing a congenital developmental disease and highlights the essential role of ZNF808 for pancreatic development in humans.