Biology subjects

van Klinken, J. B.

Publications and source records attributed to van Klinken, J. B..

3 recordsLinked to original sources

bioRxiv2025

Integrated Multi-Omics Mapping of Mitochondrial Dysfunction and Substrate Preference in Barth Syndrome Cardiac Tissue

Barth syndrome (BTHS) is a rare X-linked recessively inherited disorder caused by variants in the TAFAZZIN gene, leading to impaired conversion of monolysocardiolipin (MLCL) into mature cardiolipin (CL). Accumulation of MLCL and CL deficiency are diagnostic markers for BTHS. Clinically, BTHS includes cardiomyopathy, skeletal myopathy, neutropenia, and growth delays. Severely affected patients may require early cardiac transplants due to unpredictable cardiac phenotypes. The pathophysiological mechanisms of BTHS are poorly understood, and treatments remain symptomatic. This study analyzed heart samples from five pediatric male BTHS patients (5 months-15 years) and compared them to tissues from 24 non-failing donors (19-71 years) using an integrated omics method combining metabolomics, lipidomics, and proteomics. The analysis confirmed changes in diagnostic markers (CL and MLCL), severe mitochondrial alterations, metabolic shifts, and elevated heart-failure markers. It also revealed significant interindividual differences among BTHS patients. With this study describe a powerful analytical tool for the in-depth analysis of metabolic disorders and a solid foundation for the understanding of BTHS disease phenotypes in cardiac tissues.

molecular biology↗

bioRxiv2023

Tracer-based lipidomics identifies novel disease-specific biomarkers in mitochondrial β-oxidation disorders

Carnitine derivatives of disease-specific acyl-CoAs are the diagnostic hallmark for long-chain fatty acid oxidation disorders (lcFAOD), including carnitine shuttle deficiencies, very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MPTD). The exact consequence of accumulating lcFAO-intermediates and possible influence on cellular lipid homeostasis are, however, still unknown. To investigate the fate and cellular effects of the accumulating lcFAO-intermediates and to explore new disease markers, we used tracer-based lipidomics with deuterium-labeled oleic acid (D9-C18:1) in lcFAOD patient-derived fibroblasts. In line with previous studies, we observed a trend towards neutral lipid accumulation in lcFAOD. In addition, we detected a direct connection between the chain length and patterns of (un)saturation of accumulating acylcarnitines and the various enzyme deficiencies. Our results also identified two new candidate disease markers. Lysophosphatidylcholine(14:1) (LPC(14:1)) was specifically increased in severe VLCADD compared to mild VLCADD and control samples. This was confirmed in plasma samples showing an inverse correlation with enzyme activity, which was better than the classic diagnostic marker C14:1-carnitine. The second biomarker is an unknown lipid class, which we identified as S-(3-hydroxyacyl)cysteamines. These are hypothesized to be degradation products of the CoA moiety of accumulating 3-hydroxyacyl-CoAs. S-(3-hydroxyacyl)cysteamines were significantly increased in LCHADD compared to controls and other lcFAOD, including MTPD. Our findings suggest extensive alternative lipid metabolism in lcFAOD and confirm that lcFAOD accumulate neutral lipid species. In addition, we present two new disease markers for VLCADD and LCHADD, that may have significant relevance for disease diagnosis, prognosis, and monitoring.

molecular biology↗

bioRxiv2019

Recessive genetic effects on type 2 diabetes-related metabolites in a consanguineous population

Autozygosity, meaning inheritance of an ancestral allele in the homozygous state is known to lead bi-allelic mutations that manifest their effects through the autosomal recessive inheritance pattern. Autosomal recessive mutations are known to be the underlying cause of several Mendelian metabolic diseases, especially among the offspring of related individuals. In line with this, inbreeding coefficient of an individual as a measure of cryptic autozygosity among the general population is known to lead adverse metabolic outcomes including Type 2 diabetes (T2DM); a multifactorial metabolic disease for which the recessive genetic causes remain unknown. In order to unravel such effects for multiple metabolic facades of the disease, we investigated the relationship between the excess of homozygosity and the metabolic signature of T2DM. We included a set of 53 metabolic phenotypes, including 47 metabolites, T2DM and five T2DM risk factors, measured in a Dutch genetic isolate of 2,580 people. For 20 of these markers, we identified 29 regions of homozygous (ROHs) associated with the nominal significance of P-value < 1.0 x 10-3. By performing association according to the recessive genetic model within these selected regions, we identified and replicated two intronic variants: rs6759814 located in KCNH7 associated with valine and rs1573707 located in PTPRT associated with IDL-free cholesterol and IDL-phospholipids. Additionally, we identified a rare intronic SNV in TBR1 for which the homozygous individuals were enriched for obesity. Interestingly, all three genes are mainly neuronally expressed and pointed out the involvement of glutamergic synaptic transmission pathways in the regulation of metabolic pathways. Taken together our study underline the additional benefits of model supervised analysis, but also seconds the involvement of the central nervous system in T2DM and obesity pathogenesis.

genetics↗