Farooq, Muhammad, Lindbaek, Louise, Krogh, Nicolai ORCID: 0000-0001-8870-7091, Doganli, Canan, Keller, Cecilie, Monnich, Maren, Goncalves, Andre Bras, Sakthivel, Srinivasan, Mang, Yuan, Fatima, Ambrin, Andersen, Vivi Sogaard, Hussain, Muhammad S., Eiberg, Hans, Hansen, Lars, Kjaer, Klaus Wilbrandt, Gopalakrishnan, Jay, Pedersen, Lotte Bang, Mollgard, Kjeld, Nielsen, Henrik, Baig, Shahid M., Tommerup, Niels, Christensen, Soren Tvorup and Larsen, Lars Allan (2020). RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis. Nat. Commun., 11 (1). BERLIN: NATURE RESEARCH. ISSN 2041-1723

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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. The RRP7A a gene is involved in ribosome biogenesis. Here the authors report a homozygous missense mutation segregating with primary microcephaly, and show that this occurs via functional defects in both nucleoli and primary cilia disrupting cell proliferation and neurogenesis.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Farooq, MuhammadUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindbaek, LouiseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krogh, NicolaiUNSPECIFIEDorcid.org/0000-0001-8870-7091UNSPECIFIED
Doganli, CananUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keller, CecilieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Monnich, MarenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goncalves, Andre BrasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sakthivel, SrinivasanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mang, YuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fatima, AmbrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andersen, Vivi SogaardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hussain, Muhammad S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eiberg, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hansen, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kjaer, Klaus WilbrandtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gopalakrishnan, JayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pedersen, Lotte BangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mollgard, KjeldUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nielsen, HenrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baig, Shahid M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tommerup, NielsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Christensen, Soren TvorupUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Larsen, Lars AllanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-311295
DOI: 10.1038/s41467-020-19658-0
Journal or Publication Title: Nat. Commun.
Volume: 11
Number: 1
Date: 2020
Publisher: NATURE RESEARCH
Place of Publication: BERLIN
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELL-PROLIFERATION; PROTEIN; RNA; MUTATIONS; CILIOGENESIS; WDR62; DIFFERENTIATION; ACTIVATION; CANCER; CORTEXMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/31129

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