Molecular genetic analysis of consanguineous families with primary microcephaly identified pathogenic variants in the ASPM gene

Khan, Muzammil Ahmad; Windpassinger, Christian; Ali, Muhammad; Zubair, Muhammad; Gul, Hadia; Abbas, Safdar; Khan, Saadullah; Badar, Muhammad; Mohammad, Ramzi M.; Nawaz, Zafar

doi:10.1007/s12041-017-0759-x

Cited by 13 publications

(12 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Its mutations/translocations have also been newly associated with leukemia, developmental delay, and mental retardation. ANKLE2 is a poorly studied nuclear envelope assembly protein with its mutations associated with microcephaly 47 – 49 . CTSD is a lysosome enzyme involved in autophagy and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Autophagy mediates glucose starvation-induced glioblastoma cell quiescence and chemoresistance through coordinating cell metabolism, cell cycle, and survival

et al. 2018

View full text Add to dashboard Cite

Metabolic reprogramming is pivotal to sustain cancer growth and progression. As such dietary restriction therapy represents a promising approach to starve and treat cancers. Nonetheless, tumors are dynamic and heterogeneous populations of cells with metabolic activities modulated by spatial and temporal contexts. Autophagy is a major pathway controlling cell metabolism. It can downregulate cell metabolism, leading to cancer cell quiescence, survival, and chemoresistance. To understand treatment dynamics and provide rationales for better future therapeutic strategies, we investigated whether and how autophagy is involved in the chemo-cytotoxicity and -resistance using two commonly used human glioblastoma (GBM) cell lines U87 and U251 together with primary cancer cells from the GBM patients. Our results suggest that autophagy mediates chemoresistance through reprogramming cancer cell metabolism and promoting quiescence and survival. Further unbiased transcriptome profiling identified a number of clinically relevant pathways and genes, strongly correlated with TCGA data. Our analyses have not only reported many well-known tumor players, but also uncovered a number of genes that were not previously implicated in cancers and/or GBM. The known functions of these genes are highly suggestive. It would be of high interest to investigate their potential involvement in GBM tumorigenesis, progression, and/or drug resistance. Taken together, our results suggest that autophagy inhibition could be a viable approach to aid GBM chemotherapy and combat drug resistance.

show abstract

Section: Discussionmentioning

confidence: 99%

Autophagy mediates glucose starvation-induced glioblastoma cell quiescence and chemoresistance through coordinating cell metabolism, cell cycle, and survival

et al. 2018

View full text Add to dashboard Cite

show abstract

“…During interphase, calmodulin is in the cytoplasm and is associated with mitotic spindles during mitosis. Inhibition of cytokinesis and abnormal spindle formation takes place due to mutations in the calmodulin-binding IQ domain of the ASPM protein (Khan et al, 2017;Willingham et al, 1983). Novelty of this mutation in the Pakistani population also confirmed by visiting https:// pakmutation.kust.edu.pk/.…”

Section: Discussionmentioning

confidence: 74%

Novel Pathogenic Mutation Mapping of ASPM Gene in Consanguineous Pakistani Families with Primary Microcephaly

2023

View full text Add to dashboard Cite

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a congenitally reduced head circumference (-3 to -5 SD) and non-progressive intellectual disability. The objective of the study was to evaluate pathogenic mutations in the ASPM gene to understand etiology and molecular mechanism of primary microcephaly. Blood samples were collected from various families across different remote areas of Pakistan from February 2017 to May 2019 who were identified to be affected with primary microcephaly. DNA extraction was performed using the salting-out method; the quality and quantity of DNA were evaluated using spectrophotometry and 1% agarose gel electrophoresis, respectively in University of the Punjab. Mutation analysis was performed by whole exome sequencing from the Cologne Center for Genomics, University of Cologne. Sanger sequencing was done in University of the Punjab to confirm the pathogenic nature of mutation. A novel 4-bp deletion mutation c.3877_3880delGAGA was detected in exon 17 of the ASPM gene in two primary microcephaly affected families (A and B), which resulted in a frame shift mutation in the gene followed by truncated protein synthesis (p.Glu1293Lysfs*10), as well as the loss of the calmodulin-binding IQ domain and the Armadillo-like domain in the ASPM protein. Using the in-silico tools Mutation Taster, PROVEAN, and PolyPhen, the pathogenic effect of this novel mutation was tested; it was predicted to be “disease causing,” with high pathogenicity scores. One previously reported mutation in exon 24 (c.9730C>T) of the ASPM gene resulting in protein truncation (p.Arg3244*) was also observed in family C. Mutations in the ASPM gene are the most common cause of MCPH in most cases. Therefore, enrolling additional affected families from remote areas of Pakistan would help in identifying or mapping novel mutations in the ASPM gene of primary microcephaly.

show abstract

“…Abnormal spindle microtubule assembly (ASPM), the human ortholog of the Drosophila melanogaster 'abnormal spindle' gene (asp), was the most common mutant gene associated with microcephaly primary type 5 [35]. ASPM was essential for normal mitotic spindle function, which could correctly guide the movement of spindles and maintain symmetric division of cytoplasm in mitosis [36]. ASPM was found to up-regulate in some malignancies, such as breast cancer and gastric cancer [37].…”

Section: Discussionmentioning

confidence: 99%

Construction and validation of an eight-gene signature with great prognostic value in bladder cancer

Yan¹,

Fu²,

Guo³

et al. 2020

J. Cancer

View full text Add to dashboard Cite

Bladder cancer (BC) is one of the most common malignancies in urinary system with a common malignancy in urinary system with a high mortality and recurrence rate, so we attempt to construct a gene signature to predict the prognosis of BCs. We initially established a co-expression network by performing WGCNA analysis and further identified magenta module as key module (P = 8e-05, R2 = 0.4). Subsequently, we screened 12 genes associated with survival from the key module, which were selected to construct an eight-gene signature by establishing a LASSO Cox model. Moreover, we reckoned the risk score (RS) of each sample, through which we could divide samples into two groups (the high-risk and low-risk groups) and verify the signature, in the training set and 3 validation sets (internal test set, GSE13507and E-MTAB-4321). This signature could distinguish between the high-and low-risk patients well (survival analysis: P = 0.015; AUC: 0.61 at 1 year, 0.61 at 3 years and 0.61 at 5 years). In the validation sets, this signature also showed good performance, which was consistent with the training test. Furthermore, we plotted a nomogram to predict the possibility of the overall survival (OS) and three calibration curves to predict the effectiveness of the nomogram, which suggested good value and clinical utility of the nomogram. In conclusion, we established an eight-gene signature, which was probably effective in the prediction of prognosis of patients with BC.

show abstract

Molecular genetic analysis of consanguineous families with primary microcephaly identified pathogenic variants in the ASPM gene

Cited by 13 publications

References 20 publications

Autophagy mediates glucose starvation-induced glioblastoma cell quiescence and chemoresistance through coordinating cell metabolism, cell cycle, and survival

Autophagy mediates glucose starvation-induced glioblastoma cell quiescence and chemoresistance through coordinating cell metabolism, cell cycle, and survival

Novel Pathogenic Mutation Mapping of ASPM Gene in Consanguineous Pakistani Families with Primary Microcephaly

Construction and validation of an eight-gene signature with great prognostic value in bladder cancer

Contact Info

Product

Resources

About