Developmental Biology - SIDS|
Gene Link For Sudden Infant Death Syndrome
Newborns with a particular gene mutation can succumb to heart failure from an inability to process milk...
A new University of Washington Medical research (UW Medicine) study is the first to find a link between a genetic anomaly and some forms of Sudden Infant Death Syndrome, or SIDS.
SIDS claims more than 3,000 infants a year.
Hannele Ruohola-Baker, professor of biochemistry, University of Washington School of Medicine, headed the multi-institutional study just published in the October 11 edition of Nature Communications.
Researchers focused on mitochondrial tri-functional protein deficiency, a potentially fatal cardiac metabolic disorder caused by a genetic mutation in the gene HADHA.
Newborns with this genetic anomaly cannot metabolize milk lipids and die suddenly of cardiac arrest at a couple months of age. Lipids are a category of molecules which includes fats, cholesterol and fatty acids.
"There are multiple causes for sudden infant death syndrome. Some are environmental. But, what we're studying here is really a genetic cause of SIDS. In this particular case, it involves a defect in the enzyme that breaks down fat," says Hannele Ruohola-Baker PhD, Associate Director for UW Medicine Institute for Stem Cell and Regenerative Medicine, where her lab is located.
Jason Miklas, now postdoctoral fellow at Stanford University, was lead author on the paper. He came up with the idea when he noticed a small study examining children who couldn't process fats and who also had cardiac disease that could not be easily explained.
Miklas and Ruohola-Baker started growing heart cells in petri dishes to mimic infant heart cells in order to find out why these cells died while being grown.
"It can be very scary. If a child has a mutation, depending on that mutation, a child can die suddenly in its first few months of life," he notes. "And an autopsy wouldn't necessarily pick up why the child had passed. But now we think it might be that infant's heart stopping beating. We're no longer just trying to treat symptoms of disease," Miklas adds. "We're trying to treat the root problem. It's very gratifying to see real progress in the lab toward interventions that may one day make their way into the clinic."
In MTP deficiency, the heart cells of affected infants do not convert fats into nutrients properly. This results in a build-up of unprocessed fatty material that can disrupt heart function.
Technically, the breakdown occurs when enzymes fail to complete a process known as fatty acid oxidation. Although it is possible to screen for the genetic markers of MTP deficiency — effective treatments are still a ways off.
Ruohola-Baker sees the latest laboratory discovery as a big step towards finding ways to overcome SIDS: "There is no cure for this. But there is now hope, as we've found a new aspect of the disease that will innovate generations of novel small molecules and designed proteins, which might help future patients."
One drug the group is now focusing on is Elamipretide. Used to stimulate hearts and organs that have oxygen deficiency, it was rarely considered for helping infant hearts — until now.
Prospective parents can now be screened to see if there is a chance their child might carry this genetic mutation. Ruohola-Baker's personal interest in this research, began with her friends in her home country of Finland, whose child died of SIDS.
"It was absolutely devastating. Since then, I've been very interested in the causes for Sudden Infant Death Syndrome. It's very exciting to think that our work may contribute to future treatments, and help parents who find their children have these mutations."em>
Hannele Ruohola-Baker PhD,
Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicin; Department of Bioengineering, University of Washington; Department of Biochemistry, University of Washington, School of Medicine, Seattle, WA, USA.
Mitochondrial trifunctional protein deficiency, due to mutations in hydratase subunit A (HADHA), results in sudden infant death syndrome with no cure. To reveal the disease etiology, we generated stem cell-derived cardiomyocytes from HADHA-deficient hiPSCs and accelerated their maturation via an engineered microRNA maturation cocktail that upregulated the epigenetic regulator, HOPX. Here we report, matured HADHA mutant cardiomyocytes treated with an endogenous mixture of fatty acids manifest the disease phenotype: defective calcium dynamics and repolarization kinetics which results in a pro-arrhythmic state. Single cell RNA-seq reveals a cardiomyocyte developmental intermediate, based on metabolic gene expression. This intermediate gives rise to mature-like cardiomyocytes in control cells but, mutant cells transition to a pathological state with reduced fatty acid beta-oxidation, reduced mitochondrial proton gradient, disrupted cristae structure and defective cardiolipin remodeling. This study reveals that HADHA (tri-functional protein alpha), a monolysocardiolipin acyltransferase-like enzyme, is required for fatty acid beta-oxidation and cardiolipin remodeling, essential for functional mitochondria in human cardiomyocytes.
Jason W. Miklas, Elisa Clark, Shiri Levy, Damien Detraux, Andrea Leonard, Kevin Beussman, Megan R. Showalter, Alec T. Smith, Peter Hofsteen, Xiulan Yang, Jesse Macadangdang, Tuula Manninen, Daniel Raftery, Anup Madan, Anu Suomalainen, Deok-Ho Kim, Charles E. Murry, Oliver Fiehn, Nathan J. Sniadecki, Yuliang Wang & Hannele Ruohola-Baker.
The authors thank members of the Ruohola-Baker laboratory for helpful discussions throughout this work. This work is supported by grants from the National Institutes of Health R01GM097372, and R01GM083867 for HRB, 1P01GM081619 for C.M. and H.R.B., R01HL146436 and R01HL135143 for H.R.B. and D.H.K. and the NHLBI Progenitor Cell Biology Consortium (U01HL099997; UO1HL099993) for C.M. and H.R.B. National Science Foundation grants CBET-1509106 and CMMI-1661730 for N.S.J. A.S. was supported by the Academy of Finland and Finnish Foundation for Cardiovascular Research. We would like to thank: Dr. David Marcinek for the SS-31, BGI for their sequencing services, Bruce Conklin (UCSF, Gladstone Institute) for the WTC CRISPRi hiPSCs and pQM plasmid backbone, the Vision Core for their TEM services (P30 EY001730) and Professor Vockley and Dr. El-gharbawy for helpful discussions and advice. Scholarship support from the Wellstone Muscular Dystrophy Cooperative Research Center: U54AR065139 and the NSERC Alexander Graham Bell Graduate Scholarship for J.W.M. A.L. was supported by National Institute of Health grants F32 HL126332. S.L. was supported by the WRF Posdoctoral Fellowship Program and E.C. was supported by an NSF Graduate Research Fellowship.
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Oct 14 2019 Fetal Timeline Maternal Timeline News
Schematic of infant with the HADA mutation. LCHAD or "Long-chain L-3 hydroxyacyl-CoA dehydrogenase deficiency" - the condition in which the body can't break down certain fats. Considered a fatty acid oxidation problem, patients affected are unable to convert dietary fats into energy. iPSCs are Induced Pluripotent Stem Cells and made from skin or blood cells reprogrammed back into embryonic pluripotent cells with an unlimited ability to become any human cell needed. New 'induced pluripotent stem cell' (iPSC) technology, can increasingly refine iPSCs into cardiomyocytes (iPSC-CMs) the muscle cells (myocytes) that make up the cardiac muscle (heart muscle). Credit: Ruohola-Baker lab.