Novel STIL Compound Heterozygous Mutations Cause Severe Fetal Microcephaly and Centriolar Lengthening

Cristofoli, Francesca; Keersmaecker, B. De; Catte, Luc De; Vermeesch, Joris Robert; Esch, Hilde Van

doi:10.1159/000479666

Cited by 17 publications

(8 citation statements)

References 82 publications

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“…A mutation in the CPAP TCP domain that causes microcephaly in humans has been shown to decrease the affinity of CPAP to STIL (Cottee et al, 2013; Tang et al, 2011; Bond et al, 2005). Also, mutations in STIL that reside in the CPAP and SAS6 interacting motifs have also been identified in patients with microcephaly, although the significance of these alterations remains to be determined (Cristofoli et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

PLK4 promotes centriole duplication by phosphorylating STIL to link the procentriole cartwheel to the microtubule wall

Moyer

Holland

2019

eLife

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Centrioles play critical roles in organizing the assembly of the mitotic spindle and templating the formation of primary cilia. Centriole duplication occurs once per cell cycle and is regulated by Polo-like kinase 4 (PLK4). Although significant progress has been made in understanding centriole composition, we have limited knowledge of how PLK4 activity controls specific steps in centriole formation. Here, we show that PLK4 phosphorylates its centriole substrate STIL on a conserved site, S428, to promote STIL binding to CPAP. This phospho-dependent binding interaction is conserved in Drosophila and facilitates the stable incorporation of both STIL and CPAP into the centriole. We propose that procentriole assembly requires PLK4 to phosphorylate STIL in two different regions: phosphorylation of residues in the STAN motif allow STIL to bind SAS6 and initiate cartwheel assembly, while phosphorylation of S428 promotes the binding of STIL to CPAP, linking the cartwheel to microtubules of the centriole wall.

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Section: Discussionmentioning

confidence: 99%

PLK4 promotes centriole duplication by phosphorylating STIL to link the procentriole cartwheel to the microtubule wall

Moyer

Holland

2019

eLife

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“…Therefore, a disruption in cell cycle timing appears to be the common mode of pathogenesis underlying MCPH. Although we primarily focus on the described Short stature, seizures, intellectual disability, cortical malformations, visual impairment, motor problems, pre-mature death (3,4,11,12) sas-5 (C. elegans), ana2 (Drosophila), stil (mouse, zebrafish)…”

Section: Dissecting the Etiology Of Primary Microcephalymentioning

confidence: 99%

Dissecting the Genetic and Etiological Causes of Primary Microcephaly

2020

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Autosomal recessive primary microcephaly (MCPH; "small head syndrome") is a rare, heterogeneous disease arising from the decreased production of neurons during brain development. As of August 2020, the Online Mendelian Inheritance in Man (OMIM) database lists 25 genes (involved in molecular processes such as centriole biogenesis, microtubule dynamics, spindle positioning, DNA repair, transcriptional regulation, Wnt signaling, and cell cycle checkpoints) that are implicated in causing MCPH. Many of these 25 genes were only discovered in the last 10 years following advances in exome and genome sequencing that have improved our ability to identify disease-causing variants. Despite these advances, many patients still lack a genetic diagnosis. This demonstrates a need to understand in greater detail the molecular mechanisms and genetics underlying MCPH. Here, we briefly review the molecular functions of each MCPH gene and how their loss disrupts the neurogenesis program, ultimately demonstrating that microcephaly arises from cell cycle dysregulation. We also explore the current issues in the genetic basis and clinical presentation of MCPH as additional avenues of improving gene/variant prioritization. Ultimately, we illustrate that the detailed exploration of the etiology and inheritance of MCPH improves the predictive power in identifying previously unknown MCPH candidates and diagnosing microcephalic patients.

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“…Three different homozygous STIL mutations linked to the MCPH7 locus have been identified in patients with microcephaly: IIS-17, IIS-28, and IIS-3, all of which have been predicted to cause a truncated STIL protein (Kumar et al 2008). In human cells, the absence of functional STIL blocks centriole replication, while overexpression of STIL leads to excessive centriole formation (Cristofoli et al 2017). Microcephaly in MCPH7 patients can result from a decrease in STIL levels; this finding was supported by rescue experiments in U2OS cells, where the pGly717Glu mutation induces a reduced but non-null activity of STIL on centriole duplication (Mouden et al 2015).…”

Section: Scl/tal1-interrupting Locus Protein (Stil/mcph7)mentioning

confidence: 99%

Primary microcephaly with an unstable genome

Peng

et al. 2020

GENOME INSTAB. DIS.

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Autosomal recessive primary microcephaly, also known as MCPH, is a rare genetic condition where infants are born with small heads and brains. The causes of MCPH are often unknown or unclear. To date, 25 genes have been found to be associated with MCPH. Most of these genes serve similar roles in maintaining genome stability, being associated with centrosome and spindle function, chromosome dynamics, cell cycle regulation, cell division, brain development, neurogenesis, and/or the DNA damage response. In this review, we classify MCPH-associated genes based on their known functions, and propose potential novel functions of MCPH genes in DNA replication and/or the DNA replication stress response, and tumorigenesis. This classification provides a novel perspective on the underlying causes of MCPH and a comprehensive reference for future research.

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Novel STIL Compound Heterozygous Mutations Cause Severe Fetal Microcephaly and Centriolar Lengthening

Cited by 17 publications

References 82 publications

PLK4 promotes centriole duplication by phosphorylating STIL to link the procentriole cartwheel to the microtubule wall

PLK4 promotes centriole duplication by phosphorylating STIL to link the procentriole cartwheel to the microtubule wall

Dissecting the Genetic and Etiological Causes of Primary Microcephaly

Primary microcephaly with an unstable genome

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