Overexpression of the PLK4 Gene as a Novel Strategy for the Treatment of Autosomal Recessive Microcephaly by Improving Centrosomal Dysfunction

Xu, Yasong; Su, Zhiying; Lee, Sun; Yang, Xiao-Ning; Sun, Shiyu; Ji, Xiaofei; Ji, Yi-Zhen; Zhang, Suqing; Tian, Jie; Wu, Qichang

doi:10.1007/s12031-021-01881-z

Cited by 2 publications

(2 citation statements)

References 21 publications

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“…The gene lies 0.872Mbps away from the patient's duplication endpoint so it is unlikely to be disrupting the gene function. Pathogenic, homozygous frameshift and missense mutations in PLK4 often damage centriole biogenesis, microtubule spindle formation during mitosis, cell proliferation, viability and cause abnormal cytoskeleton formation (39)(40)(41). Specifically, these mutations often lead to increased cell mortality due to inefficient mitosis.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Phenotype-Gene Correlation in a Case of Novel Tandem 4q Microduplication With Short Stature, Speech Delay and Microcephaly

et al. 2022

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We describe a sporadic case of a pure, tandem, interstitial chromosome 4q duplication, arr[hg19] 4q28.1q32.3 (127,008,069-165,250,477) x3 in a boy born at 36 weeks of gestation. He presented with microcephaly (head circumference <1st percentile), short stature (height <2nd percentile) and poor weight gain (weight <3rd percentile). Hypospadias and horseshoe shaped kidneys were also revealed following a urinary tract ultrasound. Biochemical analysis revealed normal growth hormone and thyroid hormone levels. While gross and fine motor skill development was in line with his age, speech delay was observed. This patient adds to a group of more than 30 cases of pure 4q tandem duplication with common and differing phenotypic presentations. Using a retrospective analysis of previous case studies alongside the current case and bioinformatics analysis of the duplicated region, we deduced the most likely dosage sensitive genes for some of the major phenotypes in the patient. The positive predictive value (PPV) was calculated for each gene and phenotype and was derived by comparing the previously reported patients who have gene duplications and an associated phenotype versus those who had the gene duplications but were unaffected. Thus, the growth retardation phenotype may be associated with NAA15 duplication, speech delay with GRIA2 and microcephaly with PLK4 duplication. Functional studies will help in confirming the observations and elucidating the mechanisms. However, our study highlights the importance of analysing case reports with pure duplications in defining phenotype-gene relationships and in improving our knowledge of the function of precise chromosomal regions.

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Section: Discussionmentioning

confidence: 99%

Case Report: Phenotype-Gene Correlation in a Case of Novel Tandem 4q Microduplication With Short Stature, Speech Delay and Microcephaly

et al. 2022

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“…Some of the other known MCPH-associated mutations in centrosome duplication genes such as STIL and PLK4 have been reported to affect their protein levels (Martin et al 2014, Patwardhan et al 2018, Xu et al 2021. The effect of sas-6(L69T) mutation on SAS-6 protein levels is unknown.…”

Section: Sas-6 Protein Levels Are Altered In the Presence Of The Sas-...mentioning

confidence: 99%

A primary microcephaly-associatedsas-6mutation perturbs centrosome duplication, dendrite morphogenesis, and ciliogenesis inCaenorhabditis elegans

Bergwell

Smith

et al. 2022

Preprint

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A missense mutation within the humanSASS6gene has been linked with the incidence of primary microcephaly in a Pakistani family. However, the mechanism by which this mutation causes disease is still unclear. SASS6 protein function is conserved between humans andC. elegans. Therefore, in the present study, we usedC. elegansto model this primary microcephaly-associated mutation to determine which molecular pathways are affected by this mutation inC. elegans. The human primary microcephaly-associated mutation corresponds to SAS-6(L69T) inC. elegans. Our studies revealed that both centrosome duplication and ciliogenesis are perturbed by thesas-6(L69T)mutation. Specifically,C. eleganscarrying thesas-6(L69T)mutation exhibit an increased failure of centrosome duplication in a sensitized genetic background. Further, worms carrying this mutation also display shortened phasmid cilia, an abnormal phasmid cilia morphology, defective phasmid dendrite morphology and chemotaxis defects. Our data show that the centrosome duplication defects caused by this mutation are only uncovered in a sensitized genetic background, indicating that these defects are mild. However, the ciliogenesis defects caused by this mutation are evident in an otherwise wild-type background, indicating that they are stronger defects. Based on our findings, we propose that the ciliogenesis defects induced by this mutation are likely a more important contributing factor to the development of primary microcephaly in humans carrying this mutation than centrosome duplication defects. Thus, our studies shed light on a novel mechanism by which thesas-6(L69T)mutation could lead to the incidence of primary microcephaly in humans.

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Overexpression of the PLK4 Gene as a Novel Strategy for the Treatment of Autosomal Recessive Microcephaly by Improving Centrosomal Dysfunction

Cited by 2 publications

References 21 publications

Case Report: Phenotype-Gene Correlation in a Case of Novel Tandem 4q Microduplication With Short Stature, Speech Delay and Microcephaly

Case Report: Phenotype-Gene Correlation in a Case of Novel Tandem 4q Microduplication With Short Stature, Speech Delay and Microcephaly

A primary microcephaly-associatedsas-6mutation perturbs centrosome duplication, dendrite morphogenesis, and ciliogenesis inCaenorhabditis elegans

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