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

Nature Communications
Muhammad FarooqLars Allan Larsen

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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Citations

Aug 18, 2021·Molecular Genetics & Genomic Medicine·Sarah DuerinckxMarc Abramowicz
Aug 24, 2021·Trends in Cell Biology·Kousuke Kasahara, Masaki Inagaki

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Methods Mentioned

BETA
exome sequencing
PCR
X-ray
electrophoresis
light microscopy
immunoprecipitation
targeted mutations
co-IP
biopsy
biopsies

Software Mentioned

Chromosomal Analysis Suite ( ChAS )
ImageJ Cell Counter
Excel
SIFT
ImageJ
Olympus CellSens Dimension
Polyphen2
syngo fastView
IT
Peak Scanner

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