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Papers by Erik Schoenmakers
Antioxidants & Redox Signaling
Endocrine-Related Cancer
Adrenocortical carcinoma (ACC) is a rare aggressive malignancy with a poor outcome largely due to... more Adrenocortical carcinoma (ACC) is a rare aggressive malignancy with a poor outcome largely due to limited treatment options. Here, we propose a novel therapeutic approach through modulating intracellular free cholesterol via the liver X receptor alpha (LXRα) in combination with current first-line pharmacotherapy, mitotane. H295R and MUC-1 ACC cell lines were pretreated with LXRα inhibitors in combination with mitotane. In H295R, mitotane (20, 40 and 50 µM) induced dose-dependent cell death; however, in MUC-1, this only occurred at a supratherapeutic concentration (200 µM). LXRα inhibition potentiated mitotane-induced cytotoxicity in both cell lines. This was confirmed through use of the CompuSyn model which showed moderate pharmacological synergism and was indicative of apoptotic cell death via an increase in annexinV and cleaved-caspase 3 expression. Inhibition of LXRα was confirmed through downregulation of cholesterol efflux pumps ABCA1 and ABCG1; however, combination treatment w...
Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a caus... more Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microcephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived iPSCs to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutation-containing progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a novel micropatterned chip assay, we find that spatial self-organisation of mutation-containing progenitor cells is impaired, consistent with downregulated expression of cell-cell adhesion genes. These results reveal for the first time that thyroid hormone receptor α1 is required for normal neural progenitor cell proliferati...
Diabetes, Jun 1, 2018
Loss-of-function mutations in cause familial partial lipodystrophy type 3 (FPLD3) and severe meta... more Loss-of-function mutations in cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many patients. Missense mutations in are present in ∼1 in 500 people. Although mutations are often binarily classified as benign or deleterious, prospective functional classification of all missense variants suggests that their impact is graded. Furthermore, in testing novel mutations with both prototypic endogenous (e.g., prostaglandin J2 [PGJ2]) and synthetic ligands (thiazolidinediones, tyrosine agonists), we observed that synthetic agonists selectively rescue function of some peroxisome proliferator-activated receptor-γ (PPARγ) mutants. We report on patients with FPLD3 who harbor two such PPARγ mutations (R308P and A261E). Both PPARγ mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonists in vitro, with structural modeling providing a basis for such differential ligand-dependent responsiveness. Concor...
Thyroid : official journal of the American Thyroid Association, Jul 1, 2017
Resistance to thyroid hormone alpha (RTHα), a disorder characterized by tissue-selective hypothyr... more Resistance to thyroid hormone alpha (RTHα), a disorder characterized by tissue-selective hypothyroidism and near-normal thyroid function tests due to thyroid receptor alpha gene mutations, is rare but probably under-recognized. This study sought to correlate the clinical characteristics and response to thyroxine (T4) therapy in two adolescent RTHα patients with the properties of the THRA mutation, affecting both TRα1 and TRα2 proteins, they harbored. Clinical, auxological, biochemical, and physiological parameters were assessed in each patient at baseline and after T4 therapy. Heterozygous THRA mutations occurring de novo were identified in a 17-year-old male (patient P1; c.788C>T, p.A263V mutation) investigated for mild pubertal delay and in a 15-year-old male (patient P2; c.821T>C, p.L274P mutation) with short stature (0.4th centile), skeletal dysplasia, dysmorphic facies, and global developmental delay. Both individuals exhibited macrocephaly, delayed dentition, and constip...
Endocrine Abstracts, 2016
Endocrine Abstracts, 2016
The Journal of Clinical Endocrinology & Metabolism, 2016
Context: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism ... more Context: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken. Objective: Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. Results: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases. Conclusions: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (ϳ41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.
The Journal of clinical investigation, Jan 8, 2016
Selenium is a trace element that is essential for human health and is incorporated into more than... more Selenium is a trace element that is essential for human health and is incorporated into more than 25 human selenocysteine-containing (Sec-containing) proteins via unique Sec-insertion machinery that includes a specific, nuclear genome-encoded, transfer RNA (tRNA[Ser]Sec). Here, we have identified a human tRNA[Ser]Sec mutation in a proband who presented with a variety of symptoms, including abdominal pain, fatigue, muscle weakness, and low plasma levels of selenium. This mutation resulted in a marked reduction in expression of stress-related, but not housekeeping, selenoproteins. Evaluation of primary cells from the homozygous proband and a heterozygous parent indicated that the observed deficit in stress-related selenoprotein production is likely mediated by reduced expression and diminished 2'-O-methylribosylation at uridine 34 in mutant tRNA[Ser]Sec. Moreover, this methylribosylation defect was restored by cellular complementation with normal tRNA[Ser]Sec. This study identifie...
Clinical endocrinology, Jan 30, 2015
Nephrogenic syndrome of inappropriate antidiuresis (NSIAD), resulting from activating mutations i... more Nephrogenic syndrome of inappropriate antidiuresis (NSIAD), resulting from activating mutations in the arginine vasopressin receptor type 2 (AVPR2) is a rare cause of hyponatraemia. However, its true prevalence may be under-estimated and it should be considered in the investigation of unexplained hyponatraemia, with implications for management and targeted gene testing. We describe a structured approach to the investigation of hyponatraemia in a young patient, which allowed a diagnosis of NSIAD to be made. We review current knowledge of NSIAD, and use a structural modelling approach to further our understanding of the potential mechanisms by which the causative mutation leads to a constitutively active AVPR2. Clinical and biochemical investigation of hyponatraemia; a formal water load test with measurement of arginine vasopressin levels (AVP); sequencing of AVPR2; and computed structural modelling of the wild-type and constitutively activated mutant receptors. A 38-year-old man pres...
Oxidative Stress and Disease, 2015
Endocrine Abstracts, 2014
Antioxidants & Redox Signaling
Endocrine-Related Cancer
Adrenocortical carcinoma (ACC) is a rare aggressive malignancy with a poor outcome largely due to... more Adrenocortical carcinoma (ACC) is a rare aggressive malignancy with a poor outcome largely due to limited treatment options. Here, we propose a novel therapeutic approach through modulating intracellular free cholesterol via the liver X receptor alpha (LXRα) in combination with current first-line pharmacotherapy, mitotane. H295R and MUC-1 ACC cell lines were pretreated with LXRα inhibitors in combination with mitotane. In H295R, mitotane (20, 40 and 50 µM) induced dose-dependent cell death; however, in MUC-1, this only occurred at a supratherapeutic concentration (200 µM). LXRα inhibition potentiated mitotane-induced cytotoxicity in both cell lines. This was confirmed through use of the CompuSyn model which showed moderate pharmacological synergism and was indicative of apoptotic cell death via an increase in annexinV and cleaved-caspase 3 expression. Inhibition of LXRα was confirmed through downregulation of cholesterol efflux pumps ABCA1 and ABCG1; however, combination treatment w...
Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a caus... more Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microcephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived iPSCs to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutation-containing progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a novel micropatterned chip assay, we find that spatial self-organisation of mutation-containing progenitor cells is impaired, consistent with downregulated expression of cell-cell adhesion genes. These results reveal for the first time that thyroid hormone receptor α1 is required for normal neural progenitor cell proliferati...
Diabetes, Jun 1, 2018
Loss-of-function mutations in cause familial partial lipodystrophy type 3 (FPLD3) and severe meta... more Loss-of-function mutations in cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many patients. Missense mutations in are present in ∼1 in 500 people. Although mutations are often binarily classified as benign or deleterious, prospective functional classification of all missense variants suggests that their impact is graded. Furthermore, in testing novel mutations with both prototypic endogenous (e.g., prostaglandin J2 [PGJ2]) and synthetic ligands (thiazolidinediones, tyrosine agonists), we observed that synthetic agonists selectively rescue function of some peroxisome proliferator-activated receptor-γ (PPARγ) mutants. We report on patients with FPLD3 who harbor two such PPARγ mutations (R308P and A261E). Both PPARγ mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonists in vitro, with structural modeling providing a basis for such differential ligand-dependent responsiveness. Concor...
Thyroid : official journal of the American Thyroid Association, Jul 1, 2017
Resistance to thyroid hormone alpha (RTHα), a disorder characterized by tissue-selective hypothyr... more Resistance to thyroid hormone alpha (RTHα), a disorder characterized by tissue-selective hypothyroidism and near-normal thyroid function tests due to thyroid receptor alpha gene mutations, is rare but probably under-recognized. This study sought to correlate the clinical characteristics and response to thyroxine (T4) therapy in two adolescent RTHα patients with the properties of the THRA mutation, affecting both TRα1 and TRα2 proteins, they harbored. Clinical, auxological, biochemical, and physiological parameters were assessed in each patient at baseline and after T4 therapy. Heterozygous THRA mutations occurring de novo were identified in a 17-year-old male (patient P1; c.788C>T, p.A263V mutation) investigated for mild pubertal delay and in a 15-year-old male (patient P2; c.821T>C, p.L274P mutation) with short stature (0.4th centile), skeletal dysplasia, dysmorphic facies, and global developmental delay. Both individuals exhibited macrocephaly, delayed dentition, and constip...
Endocrine Abstracts, 2016
Endocrine Abstracts, 2016
The Journal of Clinical Endocrinology & Metabolism, 2016
Context: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism ... more Context: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken. Objective: Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. Results: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases. Conclusions: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (ϳ41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.
The Journal of clinical investigation, Jan 8, 2016
Selenium is a trace element that is essential for human health and is incorporated into more than... more Selenium is a trace element that is essential for human health and is incorporated into more than 25 human selenocysteine-containing (Sec-containing) proteins via unique Sec-insertion machinery that includes a specific, nuclear genome-encoded, transfer RNA (tRNA[Ser]Sec). Here, we have identified a human tRNA[Ser]Sec mutation in a proband who presented with a variety of symptoms, including abdominal pain, fatigue, muscle weakness, and low plasma levels of selenium. This mutation resulted in a marked reduction in expression of stress-related, but not housekeeping, selenoproteins. Evaluation of primary cells from the homozygous proband and a heterozygous parent indicated that the observed deficit in stress-related selenoprotein production is likely mediated by reduced expression and diminished 2'-O-methylribosylation at uridine 34 in mutant tRNA[Ser]Sec. Moreover, this methylribosylation defect was restored by cellular complementation with normal tRNA[Ser]Sec. This study identifie...
Clinical endocrinology, Jan 30, 2015
Nephrogenic syndrome of inappropriate antidiuresis (NSIAD), resulting from activating mutations i... more Nephrogenic syndrome of inappropriate antidiuresis (NSIAD), resulting from activating mutations in the arginine vasopressin receptor type 2 (AVPR2) is a rare cause of hyponatraemia. However, its true prevalence may be under-estimated and it should be considered in the investigation of unexplained hyponatraemia, with implications for management and targeted gene testing. We describe a structured approach to the investigation of hyponatraemia in a young patient, which allowed a diagnosis of NSIAD to be made. We review current knowledge of NSIAD, and use a structural modelling approach to further our understanding of the potential mechanisms by which the causative mutation leads to a constitutively active AVPR2. Clinical and biochemical investigation of hyponatraemia; a formal water load test with measurement of arginine vasopressin levels (AVP); sequencing of AVPR2; and computed structural modelling of the wild-type and constitutively activated mutant receptors. A 38-year-old man pres...
Oxidative Stress and Disease, 2015
Endocrine Abstracts, 2014