RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis

Muhammad Farooq, Louise Lindbæk, Nicolai Krogh, Canan Doganli, Cecilie Keller, Maren Mönnich, André Brás Gonçalves, Srinivasan Sakthivel, Yuan Mang, Ambrin Fatima, Vivi Søgaard Andersen, Muhammad S. Hussain, Hans Eiberg, Lars Hansen, Klaus Wilbrandt Kjaer, Jay Gopalakrishnan, Lotte Bang Pedersen, Kjeld Møllgård, Henrik Nielsen, Shahid. M. Baig, Niels Tommerup, Søren Tvorup Christensen () and Lars Allan Larsen ()
Additional contact information
Muhammad Farooq: University of Copenhagen
Louise Lindbæk: Universitetsparken 13
Nicolai Krogh: University of Copenhagen
Canan Doganli: University of Copenhagen
Cecilie Keller: Universitetsparken 13
Maren Mönnich: University of Copenhagen
André Brás Gonçalves: Universitetsparken 13
Srinivasan Sakthivel: University of Copenhagen
Yuan Mang: University of Copenhagen
Ambrin Fatima: National Institute for Biotechnology and Genetic Engineering PIEAS
Vivi Søgaard Andersen: Universitetsparken 13
Muhammad S. Hussain: University of Cologne
Hans Eiberg: University of Copenhagen
Lars Hansen: University of Copenhagen
Klaus Wilbrandt Kjaer: University of Copenhagen
Jay Gopalakrishnan: Heinrich-Heine-University
Lotte Bang Pedersen: Universitetsparken 13
Kjeld Møllgård: University of Copenhagen
Henrik Nielsen: University of Copenhagen
Shahid. M. Baig: National Institute for Biotechnology and Genetic Engineering PIEAS
Niels Tommerup: University of Copenhagen
Søren Tvorup Christensen: Universitetsparken 13
Lars Allan Larsen: University of Copenhagen

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Primary microcephaly (MCPH) is characterized by reduced brain size and intellectual disability. The exact pathophysiological mechanism underlying MCPH remains to be elucidated, but dysfunction of neuronal progenitors in the developing neocortex plays a major role. We identified a homozygous missense mutation (p.W155C) in Ribosomal RNA Processing 7 Homolog A, RRP7A, segregating with MCPH in a consanguineous family with 10 affected individuals. RRP7A is highly expressed in neural stem cells in developing human forebrain, and targeted mutation of Rrp7a leads to defects in neurogenesis and proliferation in a mouse stem cell model. RRP7A localizes to centrosomes, cilia and nucleoli, and patient-derived fibroblasts display defects in ribosomal RNA processing, primary cilia resorption, and cell cycle progression. Analysis of zebrafish embryos supported that the patient mutation in RRP7A causes reduced brain size, impaired neurogenesis and cell proliferation, and defective ribosomal RNA processing. These findings provide novel insight into human brain development and MCPH.

Date: 2020
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DOI: 10.1038/s41467-020-19658-0

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