Genetic Primary Microcephalies: When Centrosome Dysfunction Dictates Brain and Body Size

Farcy, Sarah; Hachour, Hassina; Bahi-Buisson, Nadia; Passemard, Sandrine

doi:10.3390/cells12131807

Cited by 3 publications

(2 citation statements)

References 331 publications

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“…One of the best-characterized organelles with a causative link to clinically relevant diseases is the centrosome. Many centrosome proteins have been implicated in neurodevelopmental disorders ( Remo et al 2020 ; Farcy et al 2023 ), but the organ and cell type specificity is mostly overlooked. For example, Aspm is a ubiquitous centrosome and spindle protein important in mitosis, and hence it may not be surprising that its mutation has been implicated in microcephaly ( Passemard et al 2016 ; Garrett et al 2020 ).…”

Section: The Role Of Organellar Heterogeneity In Diseasementioning

confidence: 99%

Pan-cellular organelles and suborganelles—from common functions to cellular diversity?

Schieweck,

Götz

2024

Genes Dev.

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Cell diversification is at the base of increasing multicellular organism complexity in phylogeny achieved during ontogeny. However, there are also functions common to all cells, such as cell division, cell migration, translation, endocytosis, exocytosis, etc. Here we revisit the organelles involved in such common functions, reviewing recent evidence of unexpected differences of proteins at these organelles. For instance, centrosomes or mitochondria differ significantly in their protein composition in different, sometimes closely related, cell types. This has relevance for development and disease. Particularly striking is the high amount and diversity of RNA-binding proteins at these and other organelles, which brings us to review the evidence for RNA at different organelles and suborganelles. We include a discussion about (sub)organelles involved in translation, such as the nucleolus and ribosomes, for which unexpected cell type-specific diversity has also been reported. We propose here that the heterogeneity of these organelles and compartments represents a novel mechanism for regulating cell diversity. One reason is that protein functions can be multiplied by their different contributions in distinct organelles, as also exemplified by proteins with moonlighting function. The specialized organelles still perform pan-cellular functions but in a cell type-specific mode, as discussed here for centrosomes, mitochondria, vesicles, and other organelles. These can serve as regulatory hubs for the storage and transport of specific and functionally important regulators. In this way, they can control cell differentiation, plasticity, and survival. We further include examples highlighting the relevance for disease and propose to examine organelles in many more cell types for their possible differences with functional relevance.

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Section: The Role Of Organellar Heterogeneity In Diseasementioning

confidence: 99%

Pan-cellular organelles and suborganelles—from common functions to cellular diversity?

Schieweck,

Götz

2024

Genes Dev.

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“…A common feature of these disorders is microcephaly, a defect that primarily affects the cerebral cortex and is associated with intellectual disability, especially when it occurs at birth (primary microcephaly) (4,5). Microcephaly primary hereditary (MCPH), a non-syndromic genetic form of primary microcephaly, is the most well-characterized subtype, for which 30 genes have been identified as causative and further referred to as “MCPH genes” (6,7). These genes are involved in centrosome biogenesis and DNA repair pathways, with patients often displaying genomic instability due to DNA damage accumulation and radiosensitivity (8,9).…”

Section: Introductionmentioning

confidence: 99%

A human-specific, concerted repression of microcephaly genes contributes to radiation-induced growth defects in forebrain organoids

Ribeiro,

Etlioglu,

Buset

et al. 2024

Preprint

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Prenatal radiation-induced DNA damage poses a significant threat to normal brain development, resulting in microcephaly which primarily affects the cerebral cortex. It is unclear which molecular mechanisms are at the basis of this defect in humans as the few mechanistic studies performed so far were done in animals. Here, we leveraged human embryonic stem cell- derived forebrain organoids as a model for human corticogenesis. Organoids were X-irradiated with a moderate and a high dose at different time points, representing very early and mid corticogenesis. Irradiation caused a dose- and developmental-timing-dependent reduction in organoid size, which was more prominent in developmentally younger organoids. This coincided with a dose-dependent canonical p53-DREAM-dependent DNA damage response (DDR), consisting of cell cycle arrest, DNA repair and apoptosis. The DDR was delayed and less pronounced in the older organoids. Besides the DDR, we observed radiation-induced premature differentiation of neural progenitors and changes in metabolism. Importantly, our transcriptomic analysis furthermore demonstrated a concerted p53-E2F4-dependent repression of primary microcephaly genes. We found that this was a human-specific feature, as it was not observed in mouse embryonic brains or primary mouse neural progenitor cells. Thus, human forebrain organoids are an excellent model to investigate prenatal DNA damage-induced microcephaly and to uncover potentially targetable human-specific pathways.

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Novel biallelic SASS6 variants associated with primary microcephaly and fetal growth restriction

Kong,

Xu,

Yin

et al. 2024

American J of Med Genetics Pt A

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Primary microcephaly is characterized by a head circumference prenatally or at birth that falls below three standard deviations from age‐, ethnic‐, and sex‐specific norms. Genetic defects are one of the underlying causes of primary microcephaly. Since 2014, five variants of the SASS6 gene have been identified as the cause of MCPH 14 in three reported families. In this study, we present the genetic findings of members of a nonconsanguineous Chinese couple with a history of microcephaly and fetal growth restriction (FGR) during their first pregnancy. Utilizing trio whole‐exome sequencing, we identified compound heterozygous variants involving a frameshift NM_194292.3:c.450_453del p.(Lys150AsnfsTer7) variant and a splice region NM_194292.3:c.1674+3A>G variant within the SASS6 gene in the affected fetus. Moreover, reverse transcriptase‐polymerase chain reaction from RNA of the mother's peripheral blood leukocytes revealed that the c.1674+3A>G variant led to the skipping of exon 14 and an inframe deletion. To the best of our knowledge, the association between FGR and SASS6‐related microcephaly has not been reported, and our findings confirm the pivotal role of SASS6 in microcephaly pathogenesis and reveal an expanded view of the phenotype and mutation spectrum associated with this gene.

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Genetic Primary Microcephalies: When Centrosome Dysfunction Dictates Brain and Body Size

Cited by 3 publications

References 331 publications

Pan-cellular organelles and suborganelles—from common functions to cellular diversity?

Pan-cellular organelles and suborganelles—from common functions to cellular diversity?

A human-specific, concerted repression of microcephaly genes contributes to radiation-induced growth defects in forebrain organoids

Novel biallelic SASS6 variants associated with primary microcephaly and fetal growth restriction

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