PUBLICATION
RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis
- Authors
- Farooq, M., Lindbæk, L., Krogh, N., Doganli, C., Keller, C., Mönnich, M., Gonçalves, A.B., Sakthivel, S., Mang, Y., Fatima, A., Andersen, V.S., Hussain, M.S., Eiberg, H., Hansen, L., Kjaer, K.W., Gopalakrishnan, J., Pedersen, L.B., Møllgård, K., Nielsen, H., Baig, S.M., Tommerup, N., Christensen, S.T., Larsen, L.A.
- ID
- ZDB-PUB-201120-149
- Date
- 2020
- Source
- Nature communications 11: 5816 (Journal)
- Registered Authors
- Doganli, Canan
- Keywords
- none
- MeSH Terms
-
- 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
- PubMed
- 33199730 Full text @ Nat. Commun.
Citation
Farooq, M., Lindbæk, L., Krogh, N., Doganli, C., Keller, C., Mönnich, M., Gonçalves, A.B., Sakthivel, S., Mang, Y., Fatima, A., Andersen, V.S., Hussain, M.S., Eiberg, H., Hansen, L., Kjaer, K.W., Gopalakrishnan, J., Pedersen, L.B., Møllgård, K., Nielsen, H., Baig, S.M., Tommerup, N., Christensen, S.T., Larsen, L.A. (2020) RRP7A links primary microcephaly to dysfunction of ribosome biogenesis, resorption of primary cilia, and neurogenesis. Nature communications. 11:5816.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping