Mitochondrial dysfunction in metabolic, cardiovascular and neurological diseases
Prof. H.J.M. Smeets
PO Box 616
6200 MD Maastricht
T: (+31) (0)43 3881995
Prof. Bert Smeets, PhD, born in 1960, biochemist, did his PhD in Human Genetics in Nijmegen. From 1995 he combines genetics research with genetic testing in Maastricht, where he is professor of Clinical Genomics, director of the Genome Center and PI of the research institutes CARIM and GROW.
His work concentrates on mitochondrial dysfunction in metabolic, cardiovascular and neurological diseases, which is reflected in > 170 peer-reviewed papers and supportive grants. The aim is to identify the genetic causes, understand the pathology, prevent the transmission and, finally, develop new therapeutic approaches for these devastating often fatal disorders.
Cardiogenetics: Elucidating the basis and molecular pathology of genetic heart disease
The aim of the Cardiogenomics programme in Maastricht is to exploit both the extensive patient cohort and novel genomics technologies to identify and functionally characterize genetic defects predominantly in inherited cardiomyopathies and heart failure.
Whole exome or whole genome sequencing can identify the genetic cause in patients, but these new technologies generate massive amounts of data on genetic variants in genes with known and unknown functions, involved in hereditary (mitochondrial) cardiomyopathies, cardiac arrhythmias and heart failure. Known key pathological mechanisms are related to defects in structural proteins, nuclear proteins, intermediate filaments and other cyoskeletal proteins, mitochondrial energy production and ion channels, but new concepts and new genes are rapidly being identified.
The challenge for the years to come is to convert data on new genes, gene defects and human genome variation in patients with genetic cardiovascular disease into functionally relevant information on the diverse pathophysiological mechanisms and clinical manifestations. As bioinformatics approaches can only provide partial solutions, a functional analysis pipeline, based on primary (fibroblast) cell cultures, induced Pluripotent Stem cells (iPS) or simple model organisms, is truly essential.
Research group: Arthur van den Wijngaard, PhD; Jos Broers, PhD; Ingrid Krapels, PhD, MD in close collaboration with the cardiologists prof. S. Heymans, PhD and prof. P. Volders, PhD
This research line focuses on the characterization of:
- Abnormalities in mitochondrial genes, gene expression and gene function in inherited and complex diseases, like neuromuscular disorders, neurological syndromes and cardiomyopathies, in human patients and animal models, but alos in therapy-predictions (radiotherapy).
- Interventions that can modulate mitochondrial activity and promote health and prevent or ameliorate disease manifestations.
- Preventing the transmission of OXPHOS disease due to mutations in the mitochondrial DNA by Preimplantation Genetic Diagnosis (PGD).
The research programme that goes from bench to bedside and back is highly technology and bioinformatics driven. It covers fundamental, translational and applied research alike. Research is conducted in close connection to and supported by disease- and patient-oriented funds, like Metakids and Ride4Kids. All research is embedded in the diagnostic work of the unit Clinical Genomics (department Clinical Genetics, Maastricht UMC+), generating a close connection to patients and patient demands.
The research team has a broad and longstanding network in the field of mitochondrial disease. The applicant was co-ordinator of the EU-FP-STREP 'Mitochondrial diseases: From Bedside to Genome to Bedside' (V. Tiranti, PhD/Prof. M. Zeviani, PhD, Milano; prof. P.F. Chinnery, PhD/Prof. D. Turnbull, PhD, Newcastle; L. van den Heuvel, PhD/Prof. J. Smeitink, PhD, Nijmegen; prof. A. Munnich, PhD, Paris).
New sequencing approaches are being developed with the Technische Universität Münich (H. Prokisch, PhD) and stem cell therapy with the Sampaolesi, PhD (Interdepartmental stem cell institute of the KU Leuven, Belgium).
Gerards et al. (2013) Exome sequencing reveals a novel Moroccan founder mutation in SLC19A3 as a new cause of early-childhood fatal Leigh syndrome. Brain. 136(Pt 3):882-90.
Sallevelt SC, et al. (2013) Preimplantation genetic diagnosis in mitochondrial DNA disorders: challenge and success. J Med Genet. 50(2):125-32.
Hellebrekers DM, et al. (2012) PGD and heteroplasmic mitochondrial DNA point mutations: a systematic review estimating the chance of healthy offspring. Hum Reprod Update 18(4):341-9.
van den Bosch BJ, et al. (2012) Defective NDUFA9 as a novel cause of neonatally fatal complex I disease. J Med Genet. 49(1):10-5.
van Tienen FH, et al. (2012) Physical activity is the key determinant of skeletal muscle mitochondrial function in type 2 diabetes. J Clin Endocrinol Metab. 97(9):3261-9.
Voets AM, et al. (2012) Transcriptional changes in OXPHOS complex I deficiency are related to anti-oxidant pathways and could explain the disturbed calcium homeostasis. Biochim Biophys Acta 1822(7):1161-8.
Gerards M, et al. (2011) Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene. Brain 134(Pt 1):210-9.