Publications by authors named "Sima Kheradmand Kia"

13 Publications

  • Page 1 of 1

The impact of pre-analytical variations on biochemical analytes stability: A systematic review.

J Clin Lab Anal 2020 Dec 1;34(12):e23551. Epub 2020 Sep 1.

Laboratory for Red Blood Cell Diagnostics, Sanquin, Amsterdam, The Netherlands.

Objective: A common problem in clinical laboratories is maintaining the stability of analytes during pre-analytical processes. The aim of this study was to systematically summarize the results of a set of studies about the biochemical analytes stability.

Methods: A literature search was performed on the Advanced search field of PubMed using the keywords: "(stability) AND (analytes OR laboratory analytes OR laboratory tests OR biochemical analytes OR biochemical tests OR biochemical laboratory tests)." A total of 56 entries were obtained. After applying the selection criteria, 20 articles were included in the study.

Results: In the 20 included references, up to 123 different analytes were assessed. The 34 analytes in order of the most frequently studied analytes were evaluated: Alanine aminotransferase, aspartate aminotransferase, potassium, triglyceride, alkaline phosphatase, creatinine, total cholesterol, albumin, lactate dehydrogenase, sodium, calcium, γ-glutamyltransferase, total bilirubin, urea, creatine kinase, inorganic phosphate, total protein, uric acid, amylase, chloride, high-density lipoprotein, magnesium, glucose, C-reactive protein, bicarbonate, ferritin, iron, lipase, transferrin, cobalamin, cortisol, folate, free thyroxine, and thyroid-stimulating hormone. Stable test results could be varied between 2 hours and 1 week according to the type of samples and/or type of blood collection tubes on a basic classification set as refrigerated or room temperature.

Conclusions: Biochemical analytes stability could be improved if the best pre-analytical approaches are used.
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http://dx.doi.org/10.1002/jcla.23551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755813PMC
December 2020

A Homozygous Mutation on the HBA1 Gene Coding for Hb Charlieu (HBA1: c.320T>C) Together with β-Thalassemia Trait Results in Severe Hemolytic Anemia.

Hemoglobin 2019 Mar 13;43(2):77-82. Epub 2019 Jun 13.

a Department of Blood Cell Research , Sanquin Research and Landsteiner Laboratory, University of Amsterdam , Amsterdam , the Netherlands.

A 4-year-old boy, a β-thalassemia (β-thal) carrier, with an unexplained severe chronic microcytic anemia was referred to us. Sequencing of the α-globin genes revealed a Hb Charlieu [α106(G13)Leu→Pro, : c.320T>C, p.Leu107Pro] mutation present on both genes. Quantitative polymerase chain reaction (qPCR) confirmed α mRNA in the proband and his parents, showing that the mutation does not affect mRNA stability. However, we were unable to detect the Hb Charlieu protein by capillary electrophoresis (CE), reverse phase electrophoresis, cation exchange electrophoresis or isoelectric focusing. Mass spectrometry (MS) allowed us to confirm the presence of the Hb Charlieu peptide in erythrocyte progenitors. These findings suggest that the mutation affects the stability of α. As hemoglobin (Hb) heat stability tests showed no abnormalities in erythrocytes, we speculated that α is already degraded during red blood cell (RBC) development. The clinical severity in the proband and the presence of new methylene blue-stained aggregates in his reticulocytes indicates that incorporation of α destabilizes Hb. This, combined with an excess of unstable free α-globins as the result of β-thal minor, results in severely impaired erythropoiesis and, as a consequence, severe and chronic microcytic anemia in the proband.
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http://dx.doi.org/10.1080/03630269.2019.1601107DOI Listing
March 2019

Sensitive Monogenic Noninvasive Prenatal Diagnosis by Targeted Haplotyping.

Am J Hum Genet 2017 Sep 24;101(3):326-339. Epub 2017 Aug 24.

Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands. Electronic address:

During pregnancy, cell-free DNA (cfDNA) in maternal blood encompasses a small percentage of cell-free fetal DNA (cffDNA), an easily accessible source for determination of fetal disease status in risk families through non-invasive procedures. In case of monogenic heritable disease, background maternal cfDNA prohibits direct observation of the maternally inherited allele. Non-invasive prenatal diagnostics (NIPD) of monogenic diseases therefore relies on parental haplotyping and statistical assessment of inherited alleles from cffDNA, techniques currently unavailable for routine clinical practice. Here, we present monogenic NIPD (MG-NIPD), which requires a blood sample from both parents, for targeted locus amplification (TLA)-based phasing of heterozygous variants selectively at a gene of interest. Capture probes-based targeted sequencing of cfDNA from the pregnant mother and a tailored statistical analysis enables predicting fetal gene inheritance. MG-NIPD was validated for 18 pregnancies, focusing on CFTR, CYP21A2, and HBB. In all cases we could predict the inherited alleles with >98% confidence, even at relatively early stages (8 weeks) of pregnancy. This prediction and the accuracy of parental haplotyping was confirmed by sequencing of fetal material obtained by parallel invasive procedures. MG-NIPD is a robust method that requires standard instrumentation and can be implemented in any clinic to provide families carrying a severe monogenic disease with a prenatal diagnostic test based on a simple blood draw.
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http://dx.doi.org/10.1016/j.ajhg.2017.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590845PMC
September 2017

Human mutations in integrator complex subunits link transcriptome integrity to brain development.

PLoS Genet 2017 May 25;13(5):e1006809. Epub 2017 May 25.

Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Integrator is an RNA polymerase II (RNAPII)-associated complex that was recently identified to have a broad role in both RNA processing and transcription regulation. Importantly, its role in human development and disease is so far largely unexplored. Here, we provide evidence that biallelic Integrator Complex Subunit 1 (INTS1) and Subunit 8 (INTS8) gene mutations are associated with rare recessive human neurodevelopmental syndromes. Three unrelated individuals of Dutch ancestry showed the same homozygous truncating INTS1 mutation. Three siblings harboured compound heterozygous INTS8 mutations. Shared features by these six individuals are severe neurodevelopmental delay and a distinctive appearance. The INTS8 family in addition presented with neuronal migration defects (periventricular nodular heterotopia). We show that the first INTS8 mutation, a nine base-pair deletion, leads to a protein that disrupts INT complex stability, while the second missense mutation introduces an alternative splice site leading to an unstable messenger. Cells from patients with INTS8 mutations show increased levels of unprocessed UsnRNA, compatible with the INT function in the 3'-end maturation of UsnRNA, and display significant disruptions in gene expression and RNA processing. Finally, the introduction of the INTS8 deletion mutation in P19 cells using genome editing alters gene expression throughout the course of retinoic acid-induced neural differentiation. Altogether, our results confirm the essential role of Integrator to transcriptome integrity and point to the requirement of the Integrator complex in human brain development.
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http://dx.doi.org/10.1371/journal.pgen.1006809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466333PMC
May 2017

Residual pyruvate kinase activity in PKLR-deficient erythroid precursors of a patient suffering from severe haemolytic anaemia.

Eur J Haematol 2017 Jun 12;98(6):584-589. Epub 2017 Apr 12.

Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, University of Amsterdam, Amsterdam, The Netherlands.

Objective: Here, we present a 7-year-old patient suffering from severe haemolytic anaemia. The most common cause of chronic hereditary non-spherocytic haemolytic anaemia is red blood cell pyruvate kinase (PK-R) deficiency. Because red blood cells rely solely on glycolysis to generate ATP, PK-R deficiency can severely impact energy supply and cause reduction in red blood cell lifespan. We determined the underlying cause of the anaemia and investigated how erythroid precursors in the patient survive.

Methods: PK activity assays, Western blot and Sanger sequencing were employed to determine the underlying cause of the anaemia. Patient erythroblasts were cultured and reticulocytes were isolated to determine PK-R and PKM2 contribution to glycolytic activity during erythrocyte development.

Results: We found a novel homozygous mutation (c.583G>A) in the PK-R coding gene (PKLR). Although this mutation did not influence PKLR mRNA production, no PK-R protein could be detected in the red blood cells nor in its precursors. In spite of the absence of PK-R, the reticulocytes of the patient exhibited 20% PK activity compared with control. Western blotting revealed that patient erythroid precursors, like controls, express residual PKM2.

Conclusions: We conclude that PKM2 rescues glycolysis in PK-R-deficient erythroid precursors.
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http://dx.doi.org/10.1111/ejh.12874DOI Listing
June 2017

Hydroxyurea responsiveness in β-thalassemic patients is determined by the stress response adaptation of erythroid progenitors and their differentiation propensity.

Haematologica 2013 May 25;98(5):696-704. Epub 2012 Oct 25.

Department of Cell Biology Erasmus MC, Rotterdam, The Netherlands.

β-thalassemia is caused by mutations in the β-globin locus resulting in loss of, or reduced, hemoglobin A (adult hemoglobin, HbA, α2β2) production. Hydroxyurea treatment increases fetal γ-globin (fetal hemoglobin, HbF, α2γ2) expression in postnatal life substituting for the missing adult β-globin and is, therefore, an attractive therapeutic approach. Patients treated with hydroxyurea fall into three categories: i) 'responders' who increase hemoglobin to therapeutic levels; (ii) 'moderate-responders' who increase hemoglobin levels but still need transfusions at longer intervals; and (iii) 'non-responders' who do not reach adequate hemoglobin levels and remain transfusion-dependent. The mechanisms underlying these differential responses remain largely unclear. We generated RNA expression profiles from erythroblast progenitors of 8 responder and 8 non-responder β-thalassemia patients. These profiles revealed that hydroxyurea treatment induced differential expression of many genes in cells from non-responders while it had little impact on cells from responders. Part of the gene program up-regulated by hydroxyurea in non-responders was already highly expressed in responders before hydroxyurea treatment. Baseline HbF expression was low in non-responders, and hydroxyurea treatment induced significant cell death. We conclude that cells from responders have adapted well to constitutive stress conditions and display a propensity to proceed to the erythroid differentiation program.
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http://dx.doi.org/10.3324/haematol.2012.074492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640112PMC
May 2013

RTTN mutations link primary cilia function to organization of the human cerebral cortex.

Am J Hum Genet 2012 Sep 30;91(3):533-40. Epub 2012 Aug 30.

Department of Clinical Genetics, Erasmus University Medical Center (Erasmus MC), P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.

Polymicrogyria is a malformation of the developing cerebral cortex caused by abnormal organization and characterized by many small gyri and fusion of the outer molecular layer. We have identified autosomal-recessive mutations in RTTN, encoding Rotatin, in individuals with bilateral diffuse polymicrogyria from two separate families. Rotatin determines early embryonic axial rotation, as well as anteroposterior and dorsoventral patterning in the mouse. Human Rotatin has recently been identified as a centrosome-associated protein. The Drosophila melanogaster homolog of Rotatin, Ana3, is needed for structural integrity of centrioles and basal bodies and maintenance of sensory neurons. We show that Rotatin colocalizes with the basal bodies at the primary cilium. Cultured fibroblasts from affected individuals have structural abnormalities of the cilia and exhibit downregulation of BMP4, WNT5A, and WNT2B, which are key regulators of cortical patterning and are expressed at the cortical hem, the cortex-organizing center that gives rise to Cajal-Retzius (CR) neurons. Interestingly, we have shown that in mouse embryos, Rotatin colocalizes with CR neurons at the subpial marginal zone. Knockdown experiments in human fibroblasts and neural stem cells confirm a role for RTTN in cilia structure and function. RTTN mutations therefore link aberrant ciliary function to abnormal development and organization of the cortex in human individuals.
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http://dx.doi.org/10.1016/j.ajhg.2012.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511998PMC
September 2012

Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors.

Am J Hum Genet 2011 Aug;89(2):265-76

Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands.

We describe a syndrome of primary microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes in two unrelated consanguineous families with at least three affected children. Linkage analysis revealed a region on chromosome 18 with a significant LOD score of 4.3. In this area, two homozygous nonconserved missense mutations in immediate early response 3 interacting protein 1 (IER3IP1) were found in patients from both families. IER3IP1 is highly expressed in the fetal brain cortex and fetal pancreas and is thought to be involved in endoplasmic reticulum stress response. We reported one of these families previously in a paper on Wolcott-Rallison syndrome (WRS). WRS is characterized by increased apoptotic cell death as part of an uncontrolled unfolded protein response. Increased apoptosis has been shown to be a cause of microcephaly in animal models. An autopsy specimen from one patient showed increased apoptosis in the cerebral cortex and pancreas beta cells, implicating premature cell death as the pathogenetic mechanism. Both patient fibroblasts and control fibroblasts treated with siRNA specific for IER3IP1 showed an increased susceptibility to apoptotic cell death under stress conditions in comparison to controls. This directly implicates IER3IP1 in the regulation of cell survival. Identification of IER3IP1 mutations sheds light on the mechanisms of brain development and on the pathogenesis of infantile epilepsy and early-onset permanent diabetes.
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http://dx.doi.org/10.1016/j.ajhg.2011.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155199PMC
August 2011

EZH2-dependent chromatin looping controls INK4a and INK4b, but not ARF, during human progenitor cell differentiation and cellular senescence.

Epigenetics Chromatin 2009 Dec 2;2(1):16. Epub 2009 Dec 2.

Department of Biochemistry, Center for Biomedical Genetics, Erasmus University Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands.

Background: The INK4b-ARF-INK4a tumour suppressor locus controls the balance between progenitor cell renewal and cancer. In this study, we investigated how higher-order chromatin structure modulates differential expression of the human INK4b-ARF-INK4a locus during progenitor cell differentiation, cellular ageing and senescence of cancer cells.

Results: We found that INK4b and INK4a, but not ARF, are upregulated following the differentiation of haematopoietic progenitor cells, in ageing fibroblasts and in senescing malignant rhabdoid tumour cells. To investigate the underlying molecular mechanism we analysed binding of polycomb group (PcG) repressive complexes (PRCs) and the spatial organization of the INK4b-ARF-INK4a locus. In agreement with differential derepression, PcG protein binding across the locus is discontinuous. As we described earlier, PcG repressors bind the INK4a promoter, but not ARF. Here, we identified a second peak of PcG binding that is located approximately 3 kb upstream of the INK4b promoter. During progenitor cell differentiation and ageing, PcG silencer EZH2 attenuates, causing loss of PRC binding and transcriptional activation of INK4b and INK4a. The expression pattern of the locus is reflected by its organization in space. In the repressed state, the PRC-binding regions are in close proximity, while the intervening chromatin harbouring ARF loops out. Down regulation of EZH2 causes release of the approximately 35 kb repressive chromatin loop and induction of both INK4a and INK4b, whereas ARF expression remains unaltered.

Conclusion: PcG silencers bind and coordinately regulate INK4b and INK4a, but not ARF, during a variety of physiological processes. Developmentally regulated EZH2 levels are one of the factors that can determine the higher order chromatin structure and expression pattern of the INK4b-ARF-INK4a locus, coupling human progenitor cell differentiation to proliferation control. Our results revealed a chromatin looping mechanism of long-range control and argue against models involving homogeneous spreading of PcG silencers across the INK4b-ARF-INK4a locus.
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http://dx.doi.org/10.1186/1756-8935-2-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225837PMC
December 2009

SWI/SNF mediates polycomb eviction and epigenetic reprogramming of the INK4b-ARF-INK4a locus.

Mol Cell Biol 2008 May 10;28(10):3457-64. Epub 2008 Mar 10.

Department of Biochemistry, Center for Biomedical Genetics, Erasmus University Medical Center, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.

Stable silencing of the INK4b-ARF-INK4a tumor suppressor locus occurs in a variety of human cancers, including malignant rhabdoid tumors (MRTs). MRTs are extremely aggressive cancers caused by the loss of the hSNF5 subunit of the SWI/SNF chromatin-remodeling complex. We found previously that, in MRT cells, hSNF5 is required for p16(INK4a) induction, mitotic checkpoint activation, and cellular senescence. Here, we investigated how the balance between Polycomb group (PcG) silencing and SWI/SNF activation affects epigenetic control of the INK4b-ARF-INK4a locus in MRT cells. hSNF5 reexpression in MRT cells caused SWI/SNF recruitment and activation of p15(INK4b) and p16(INK4a), but not of p14(ARF). Gene activation by hSNF5 is strictly dependent on the SWI/SNF motor subunit BRG1. SWI/SNF mediates eviction of the PRC1 and PRC2 PcG silencers and extensive chromatin reprogramming. Concomitant with PcG complex removal, the mixed lineage leukemia 1 (MLL1) protein is recruited and active histone marks supplant repressive ones. Strikingly, loss of PcG complexes is accompanied by DNA methyltransferase DNMT3B dissociation and reduced DNA methylation. Thus, various chromatin states can be modulated by SWI/SNF action. Collectively, these findings emphasize the close interconnectivity and dynamics of diverse chromatin modifications in cancer and gene control.
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http://dx.doi.org/10.1128/MCB.02019-07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2423153PMC
May 2008

Two de novo mutations in the Na,K-ATPase gene ATP1A2 associated with pure familial hemiplegic migraine.

Eur J Hum Genet 2006 May;14(5):555-60

Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands, and Department of Neurology, Dr Lütfi Kirdar State Hospital, Maltepe, Istanbul, Turkey.

Familial hemiplegic migraine (FHM) is a rare autosomal dominantly inherited subtype of migraine, in which hemiparesis occurs during the aura. The majority of the families carry mutations in the CACNA1A gene on chromosome 19p13 (FHM1). About 20% of FHM families is linked to chromosome 1q23 (FHM2), and has mutations in the ATP1A2 gene, encoding the alpha2-subunit of the Na,K-ATPase. Mutation analysis in a Dutch and a Turkish family with pure FHM revealed two novel de novo missense mutations, R593W and V628M, respectively. Cellular survival assays support the hypothesis that both mutations are disease-causative. The identification of the first de novo mutations underscores beyond any doubt the involvement of the ATP1A2 gene in FHM2.
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http://dx.doi.org/10.1038/sj.ejhg.5201607DOI Listing
May 2006

Cancer-associated mutations in chromatin remodeler hSNF5 promote chromosomal instability by compromising the mitotic checkpoint.

Genes Dev 2005 Mar;19(6):665-70

Department of Molecular and Cell Biology, Leiden University Medical Centre, 2300 RA Leiden, The Netherlands.

The hSNF5 subunit of human SWI/SNF ATP-dependent chromatin remodeling complexes is a tumor suppressor that is inactivated in malignant rhabdoid tumors (MRTs). Here, we report that loss of hSNF5 function in MRT-derived cells leads to polyploidization and chromosomal instability. Re-expression of hSNF5 restored the coupling between cell cycle progression and ploidy checkpoints. In contrast, cancer-associated hSNF5 mutants harboring specific single amino acid substitutions exacerbated poly- and aneuploidization, due to abrogated chromosome segregation. We found that hSNF5 activates the mitotic checkpoint through the p16INK4a-cyclinD/CDK4-pRb-E2F pathway. These results establish that poly- and aneuploidy of tumor cells can result from mutations in a chromatin remodeler.
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http://dx.doi.org/10.1101/gad.335805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1065719PMC
March 2005