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

Nat Commun. 2020 Nov 16;11(1):5816. doi: 10.1038/s41467-020-19658-0.

Muhammad Farooq ¹ ², Louise Lindbæk ³, Nicolai Krogh ¹, Canan Doganli ¹, Cecilie Keller ³, Maren Mönnich ¹, André Brás Gonçalves ³, Srinivasan Sakthivel ¹, Yuan Mang ¹, Ambrin Fatima ⁴, Vivi Søgaard Andersen ³, Muhammad S Hussain ⁵ ⁶, Hans Eiberg ¹, Lars Hansen ¹, Klaus Wilbrandt Kjaer ¹, Jay Gopalakrishnan ⁷, Lotte Bang Pedersen ³, Kjeld Møllgård ¹, Henrik Nielsen ¹, Shahid M Baig ⁴, Niels Tommerup ¹, Søren Tvorup Christensen ⁸, Lars Allan Larsen ⁹

Affiliations

1 Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen, Denmark.
2 Department of Biochemistry and Biotechnology, The Islamia University of Bahawalpur, Baghdad ul Jadeed Campus, 63100, Bahawalpur, Punjab, Pakistan.
3 Department of Biology, University of Copenhagen, Universitetsparken 13, DK-2100, Copenhagen, Denmark.
4 Human Molecular Genetics Laboratory; Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering PIEAS, Jhang Road, 38000, Faisalabad, Punjab, Pakistan.
5 Institute of Biochemistry I, University of Cologne, Joseph-Stelzmann-Strasse 52, D50931, Cologne, Germany.
6 Cologne Center for Genomics and Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Strasse 21, D50931, Cologne, Germany.
7 Institute of Human Genetics, Universitätsstrasse 1, Heinrich-Heine-University, D-40225, Düsseldorf, Germany.
8 Department of Biology, University of Copenhagen, Universitetsparken 13, DK-2100, Copenhagen, Denmark. [email protected].
9 Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3, DK-2200, Copenhagen, Denmark. [email protected].

PMID: 33199730 DOI: 10.1038/s41467-020-19658-0

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.

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