Novel compound heterozygous variants in PLK4 identified in a patient with autosomal recessive microcephaly and chorioretinopathy

Tsutsumi, Makiko; Yokoi, Setsuri; Miya, Fuyuki; Miyata, Masafumi; Kato, Mitsuhiro; Okamoto, Nobuhiko; Tsunoda, Tatsuhiko; Yamasaki, Mami; Kanemura, Yonehiro; Kosaki, Kenjiro; Saitoh, Shinji; Kurahashi, Hiroki

doi:10.1038/ejhg.2016.119

Cited by 13 publications

(14 citation statements)

References 20 publications

(19 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While depletion of STIL in human cells blocks centriole duplication, overexpression of the protein results in the formation of multiple daughter centrioles around a single mother centriole [Kitagawa et al, 2011;Tang et al, 2011;Arquint et al, 2012;Arquint and Nigg, 2014], a phenotype reminiscent of those observed for both hsSAS-6 and PLK4 overexpression [Habedanck et al, 2005;Leidel et al, 2005;Kleylein-Sohn et al, 2007;Peel et al, 2007;Rodrigues-Martins et al, 2007;Strnad et al, 2007;Cunha-Ferreira et al, 2009;Rogers et al, 2009;Marthiens et al, 2013;Coelho et al, 2015]. Interestingly, mutations in PLK4 have been associated with primordial dwarfism and retinopathy/chorioretinopathy, thus extending the clinical spectrum correlated to centriole de- fects [Martin et al, 2014;Shaheen et al, 2014;Tsutsumi et al, 2016]. For the first time, Kumar et al [2009] reported the association between homozygous mutations in STIL and autosomal recessive primary MC.…”

Section: Discussionmentioning

confidence: 99%

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

Cristofoli

Keersmaecker²,

Catte³

et al. 2017

Mol Syndromol

View full text Add to dashboard Cite

STIL (SCL/TAL1 interrupting locus) is a core component of the centriole duplication process. <i>STIL</i> mutations have been associated with both autosomal recessive primary microcephaly (MCPH) and holoprosencephaly. In this report, we describe a family with multiple miscarriages and 2 terminations of pregnancy due to marked fetal microcephaly, delayed cortical gyrification, and dysgenesis of the corpus callosum. Whole exome sequencing allowed us to identify novel compound heterozygous mutations in <i>STIL.</i> The mutations lie, respectively, in the CPAP/CENPJ and the hsSAS6 interacting domains of STIL. M-phase synchronized amniocytes from both affected fetuses did not display an aberrant number of centrioles, as shown previously for either STIL-depleted or overexpressing cells. However, we observed an elongation of at least 1 centriole for each duplicated centrosome. These preliminary results may point to a novel mechanism causing MCPH and embryonic lethality in humans.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Cristofoli

Keersmaecker²,

Catte³

et al. 2017

Mol Syndromol

View full text Add to dashboard Cite

show abstract

“…Additionally, we have identified a mechanism of apical centriole anchoring that appears to compensate for centriole duplication defects in NSCs by promoting apical retention. It will be interesting to investigate whether, the partial loss-of-function mutations in Plk4 described in humans, which cause microcephaly and dwarfism, support centriole retention at the apical cortex of NSCs (Martin et al., 2014, Tsutsumi et al., 2016, Shaheen et al., 2014). This might be beneficial not only by conferring the capacity to assemble primary cilia but also to ensure stem cell viability due to the presence of a centriole (Lambrus and Holland, 2017).…”

Section: Discussionmentioning

confidence: 99%

Plk4 Regulates Centriole Asymmetry and Spindle Orientation in Neural Stem Cells

et al. 2019

View full text Add to dashboard Cite

Summary Defects in mitotic spindle orientation (MSO) disrupt the organization of stem cell niches impacting tissue morphogenesis and homeostasis. Mutations in centrosome genes reduce MSO fidelity, leading to tissue dysplasia and causing several diseases such as microcephaly, dwarfism, and cancer. Whether these mutations perturb spindle orientation solely by affecting astral microtubule nucleation or whether centrosome proteins have more direct functions in regulating MSO is unknown. To investigate this question, we analyzed the consequences of deregulating Plk4 (the master centriole duplication kinase) activity in Drosophila asymmetrically dividing neural stem cells. We found that Plk4 functions upstream of MSO control, orchestrating centriole symmetry breaking and consequently centrosome positioning. Mechanistically, we show that Plk4 acts through Spd2 phosphorylation, which induces centriole release from the apical cortex. Overall, this work not only reveals a role for Plk4 in regulating centrosome function but also links the centrosome biogenesis machinery with the MSO apparatus.

show abstract

“…Blood samples from the study subjects were obtained with informed consent in accordance with local institutional review board guidelines. An Epstein-Barr virus (EBV) transformed Lymphoblastoid cell line (LCL) was established from the peripheral blood derived from the patient as described previously [6]. Conventional G-banding and fluorescence in situ hybridization (FISH) analyses were performed using LCL.…”

Section: Introductionmentioning

confidence: 99%

A female patient with retinoblastoma and severe intellectual disability carrying an X;13 balanced translocation without rearrangement in the RB1 gene: a case report

et al. 2019

Self Cite

View full text Add to dashboard Cite

BackgroundFemale carriers of a balanced X; autosome translocation generally undergo selective inactivation of the normal X chromosome. This is because inactivation of critical genes within the autosomal region of the derivative translocation chromosome would compromise cellular function. We here report a female patient with bilateral retinoblastoma and a severe intellectual disability who carries a reciprocal X-autosomal translocation.Case presentationCytogenetic and molecular analyses, a HUMARA (Human androgen receptor) assay, and methylation specific PCR (MSP) and bisulfite sequencing were performed using peripheral blood samples from the patient. The patient’s karyotype was 46,X,t(X;13)(q28;q14.1) by G-banding analysis. Further cytogenetic analysis located the entire RB1 gene and its regulatory region on der(X) with no translocation disruption. The X-inactivation pattern in the peripheral blood was highly skewed but not completely selected. MSP and deep sequencing of bisulfite-treated DNA revealed that an extensive 13q region, including the RB1 promoter, was unusually methylated in a subset of cells.ConclusionsThe der(X) region harboring the RB1 gene was inactivated in a subset of somatic cells, including the retinal cells, in the patient subject which acted as the first hit in the development of her retinoblastoma. In addition, the patient’s intellectual disability may be attributable to the inactivation of the der(X), leading to a 13q deletion syndrome-like phenotype, or to an active X-linked gene on der (13) leading to Xq28 functional disomy.

show abstract

Novel compound heterozygous variants in PLK4 identified in a patient with autosomal recessive microcephaly and chorioretinopathy

Cited by 13 publications

References 20 publications

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

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

Plk4 Regulates Centriole Asymmetry and Spindle Orientation in Neural Stem Cells

A female patient with retinoblastoma and severe intellectual disability carrying an X;13 balanced translocation without rearrangement in the RB1 gene: a case report

Contact Info

Product

Resources

About