RRC ID 63190
Author Farooq M, Lindbæk L, Krogh N, Doganli C, Keller C, Mönnich M, Gonçalves AB, Sakthivel S, Mang Y, Fatima A, Andersen VS, Hussain MS, Eiberg H, Hansen L, Kjaer KW, Gopalakrishnan J, Pedersen LB, Møllgård K, Nielsen H, Baig SM, Tommerup N, Christensen ST, Larsen LA.
Title RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis.
Journal Nat Commun
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.
Volume 11(1)
Pages 5816
Published 2020-11-16
DOI 10.1038/s41467-020-19658-0
PII 10.1038/s41467-020-19658-0
PMID 33199730
PMC PMC7670429
MeSH Adult Animals Base Sequence Brain / embryology Brain / pathology Cell Cycle Cell Nucleolus / metabolism Centrosome / metabolism Cilia / metabolism* Female Fibroblasts / metabolism Fibroblasts / pathology Humans Male Mice Microcephaly / genetics* Mutation / genetics Neural Stem Cells / metabolism Neurogenesis* Nuclear Proteins / metabolism Organelle Biogenesis* Pakistan Pedigree Protein Binding RNA Processing, Post-Transcriptional RNA, Ribosomal / genetics RNA-Binding Proteins / genetics* RNA-Binding Proteins / metabolism Ribosomes / metabolism* Zebrafish / embryology
IF 12.121
Human and Animal Cells P19.CL6(RCB1539)