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

Muhammad Farooq,Lars Allan Larsen,Lars Hansen,Søren Tvorup Christensen,Kjeld Møllgård,Vivi Søgaard Andersen,Maren Mönnich,Louise Lindbæk,Henrik Nielsen,Hans Eiberg,S Sakthivel ,Nicolai Krogh,Muhammad Sajid Hussain ,Klaus Kjaer ,Shahid Mahmood Baig ,Jay Gopalakrishnan,Ambrin Fatima,Canan Doğanlı ,André Gonçalves ,Yuan Mang,Niels Tommerup,Charlotte Keller ,Lotte B Pedersen

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.

Highlights

Primary microcephaly (MCPH) is characterized by reduced brain size and intellectual disability
RNA-processing protein 7 homolog A (RRP7A) localizes to centrosomes and the primary cilium in addition to its known nucleolar localization, and our results show that mutation or depletion of RRP7A causes ribosomal RNAprocessing defects and retarded second wave of resorption of primary cilia leading to delayed S-phase entry and progression
Measurements of the head circumference (HC) in eight affected individuals revealed a reduction in HC ranging from −6 to

Summary

Introduction

Primary microcephaly (MCPH) is characterized by reduced brain size and intellectual disability. 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. MCPH is caused by mutation in one of at least 19 genes, which encode proteins essential for centrosome and cilium biogenesis and various functions in transcriptional regulation, DNA damage responses, cell cycle progression as well as cell migration, differentiation, and apoptosis[6,7,8].

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