Sanford Childrens Health Research Center

Sioux Falls, SD, United States

Sanford Childrens Health Research Center

Sioux Falls, SD, United States
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Getty A.L.,University of Rochester | Benedict J.W.,University of Rochester | Pearce D.A.,University of Rochester | Pearce D.A.,Sanford Childrens Health Research Center | Pearce D.A.,University of South Dakota
Experimental Cell Research | Year: 2011

Juvenile neuronal ceroid lipofuscinosis (JNCL) is a pediatric lysosomal storage disorder characterized by accumulation of autofluorescent storage material and neurodegeneration, which result from mutations in CLN3. The function of CLN3, a lysosomal membrane protein, is currently unknown. We report that CLN3 interacts with cytoskeleton-associated nonmuscle myosin-IIB. Both CLN3 and myosin-IIB are ubiquitously expressed, yet mutations in either produce dramatic consequences in the CNS such as neurodegeneration in JNCL patients and Cln3-/- mouse models, or developmental deficiencies in Myh10-/- mice, respectively. A scratch assay revealed a migration defect associated with Cln3-/- cells. Inhibition of nonmuscle myosin-II with blebbistatin in WT cells resulted in a phenotype that mimics the Cln3-/- migration defect. Moreover, inhibiting lysosome function by treating cells with chloroquine exacerbated the migration defect in Cln3-/-. Cln3-/- cells traversing a transwell filter under gradient trophic factor conditions displayed altered migration, further linking lysosomal function and cell migration. The myosin-IIB distribution in Cln3-/- cells is elongated, indicating a cytoskeleton defect caused by the loss of CLN3. In summary, cells lacking CLN3 have defects that suggest altered myosin-IIB activity, supporting a functional and physical interaction between CLN3 and myosin-IIB. We propose that the migration defect in Cln3-/- results, in part, from the loss of the CLN3-myosin-IIB interaction. © 2010 Elsevier Inc.


Harris W.S.,University of South Dakota | Harris W.S.,OmegaQuant LLC | Harris W.S.,Health Diagnostics Laboratory IncSD | Harris W.S.,Sanford Health Research Center | And 2 more authors.
Journal of Perinatology | Year: 2015

Long-chain polyunsaturated fatty acids (LCPUFA) including docosahexaenoic acid (DHA) are essential for normal vision and neurodevelopment. DHA accretion in utero occurs primarily in the last trimester of pregnancy to support rapid growth and brain development. Premature infants, born before this process is complete, are relatively deficient in this essential fatty acid. Very low birth weight (VLBW) infants remain deficient for a long period of time due to ineffective conversion from precursor fatty acids, lower fat stores and a limited nutritional provision of DHA after birth. In addition to long-term visual and neurodevelopmental risks, VLBW infants have significant morbidity and mortality from diseases specific to premature birth, including bronchopulmonary dysplasia, necrotizing enterocolitis, and retinopathy of prematurity. There is increasing evidence that DHA has protective benefits against these disease states. The aim of this article is to identify the unique needs of premature infants, review the current recommendations for LCPUFA provision in infants and discuss the caveats and innovative new ways to overcome the DHA deficiency through postnatal supplementation, with the long-term goal of improving morbidity and mortality in this at-risk population. © 2015 Nature America, Inc.


Miller J.N.,Sanford Childrens Health Research Center | Miller J.N.,University of South Dakota | Chan C.-H.,Sanford Childrens Health Research Center | Pearce D.A.,Sanford Childrens Health Research Center | Pearce D.A.,University of South Dakota
Human Molecular Genetics | Year: 2013

Neuronal ceroid lipofuscinosis (NCL), commonly referred to as Batten disease, is a group of autosomal recessive neurodegenerative diseases of childhood characterized by seizures, blindness, motor and cognitive decline and premature death. Currently, there are over 400 known mutations in 14 different genes, leading to five overlapping clinical variants of NCL. A large portion of these mutations lead to premature stop codons (PTCs) and are predicted to predispose mRNA transcripts to nonsense-mediated decay (NMD). Nonsense-mediated decay is associated with a number of other genetic diseases and is an important regulator of disease pathogenesis. We contend that NMD targets PTCs in NCL gene transcripts for degradation. A number of PTC mutations in CLN1, CLN2 and CLN3 lead to a significant decrease in mRNA transcripts and a corresponding decrease in protein levels and function in patient-derived lymphoblast cell lines. Inhibiting NMD leads to an increased transcript level, and where protein function is known, increased activity. Treatment with read-through drugs also leads to increased protein function. Thus, NMD provides a promising therapeutic target that would allow read-through of transcripts to enhance protein function and possibly ameliorate Batten disease pathogenesis. © The Author 2013. Published by Oxford University Press.


Miller J.N.,University of South Dakota | Miller J.N.,Sanford Childrens Health Research Center | Pearce D.A.,University of South Dakota | Pearce D.A.,Sanford Childrens Health Research Center
Mutation Research - Reviews in Mutation Research | Year: 2014

Eukaryotic cells utilize various RNA quality control mechanisms to ensure high fidelity of gene expression, thus protecting against the accumulation of nonfunctional RNA and the subsequent production of abnormal peptides. Messenger RNAs (mRNAs) are largely responsible for protein production, and mRNA quality control is particularly important for protecting the cell against the downstream effects of genetic mutations. Nonsense-mediated decay (NMD) is an evolutionarily conserved mRNA quality control system in all eukaryotes that degrades transcripts containing premature termination codons (PTCs). By degrading these aberrant transcripts, NMD acts to prevent the production of truncated proteins that could otherwise harm the cell through various insults, such as dominant negative effects or the ER stress response. Although NMD functions to protect the cell against the deleterious effects of aberrant mRNA, there is a growing body of evidence that mutation-, codon-, gene-, cell-, and tissue-specific differences in NMD efficiency can alter the underlying pathology of genetic disease. In addition, the protective role that NMD plays in genetic disease can undermine current therapeutic strategies aimed at increasing the production of full-length functional protein from genes harboring nonsense mutations. Here, we review the normal function of this RNA surveillance pathway and how it is regulated, provide current evidence for the role that it plays in modulating genetic disease phenotypes, and how NMD can be used as a therapeutic target. © 2014 Elsevier B.V.


Doorn J.M.,University of South Dakota | Doorn J.M.,Sanford Childrens Health Research Center | Kruer M.C.,University of South Dakota | Kruer M.C.,Sanford Childrens Health Research Center
Current Neurology and Neuroscience Reports | Year: 2013

Neurodegeneration with brain iron accumulation (NBIA) comprises a group of brain iron deposition syndromes that lead to mixed extrapyramidal features and progressive dementia. Historically, there has not been a clearly identifiable molecular cause for many patients with clinical and radiologic features of NBIA. Recent discoveries have shown that mutations in C19orf12 or WDR45 can lead to NBIA. C19orf12 mutations are inherited in an autosomal recessive manner, and lead to a syndrome similar to that caused by mutations in PANK2 or PLA2G6. In contrast, WDR45 mutations lead to a distinct form of NBIA characterized by spasticity and intellectual disability in childhood followed by the subacute onset of dystonia-parkinsonism in adulthood. WDR45 mutations act in an X-linked dominant manner. Although the function of C19orf12 is largely unknown, WDR45 plays a key role in autophagy. Each of these new forms of NBIA thus leads to a distinct clinical syndrome, and together they implicate new cellular pathways in the pathogenesis of these disorders. © 2013 Springer Science+Business Media New York.


Carcel-Trullols J.,Sanford Childrens Health Research Center | Kovacs A.D.,Sanford Childrens Health Research Center | Pearce D.A.,Sanford Childrens Health Research Center | Pearce D.A.,University of South Dakota
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2015

The fatal, primarily childhood neurodegenerative disorders, neuronal ceroid lipofuscinoses (NCLs), are currently associated with mutations in 13 genes. The protein products of these genes (CLN1 to CLN14) differ in their function and their intracellular localization. NCL-associated proteins have been localized mostly in lysosomes (CLN1, CLN2, CLN3, CLN5, CLN7, CLN10, CLN12 and CLN13) but also in the Endoplasmic Reticulum (CLN6 and CLN8), or in the cytosol associated to vesicular membranes (CLN4 and CLN14). Some of them such as CLN1 (palmitoyl protein thioesterase 1), CLN2 (tripeptidyl-peptidase 1), CLN5, CLN10 (cathepsin D), and CLN13 (cathepsin F), are lysosomal soluble proteins; others like CLN3, CLN7, and CLN12, have been proposed to be lysosomal transmembrane proteins. In this review, we give our views and attempt to summarize the proposed and confirmed functions of each NCL protein and describe and discuss research results published since the last review on NCL proteins. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)". © 2014 Elsevier B.V.


Kim D.I.,Sanford Childrens Health Research Center | Kc B.,Sanford Childrens Health Research Center | Kc B.,University of South Dakota | Roux K.J.,Sanford Childrens Health Research Center | Roux K.J.,University of South Dakota
Biological Chemistry | Year: 2015

Cell nuclei are physically integrated with the cytoskeleton through the linker of nucleoskeleton and cytoskeleton (LINC) complex, a structure that spans the nuclear envelope to link the nucleoskeleton and cytoskeleton. Outer nuclear membrane KASH domain proteins and inner nuclear membrane SUN domain proteins interact to form the core of the LINC complex. In this review, we provide a comprehensive analysis of the reported protein-protein interactions for KASH and SUN domain proteins. This critical structure, directly connecting the genome with the rest of the cell, contributes to a myriad of cellular functions and, when perturbed, is associated with human disease. © 2015 by De Gruyter.


Lee L.,Sanford Childrens Health Research Center | Lee L.,University of South Dakota
Gene | Year: 2011

Motile cilia and flagella are organelles that, historically, have been poorly understood and inadequately investigated. However, cilia play critical roles in fluid clearance in the respiratory system and the brain, and flagella are required for sperm motility. Genetic studies involving human patients and mouse models of primary ciliary dyskinesia over the last decade have uncovered a number of important ciliary proteins and have begun to elucidate the mechanisms underlying ciliary motility. When combined with genetic, biochemical, and cell biological studies in Chlamydomonas reinhardtii, these mammalian genetic analyses begin to reveal the mechanisms by which ciliary motility is regulated. © 2010 Elsevier B.V.


Bergeron M.F.,Sanford Sports Science Institute | Bergeron M.F.,University of South Dakota | Bergeron M.F.,Sanford Childrens Health Research Center
Journal of Orthopaedic and Sports Physical Therapy | Year: 2014

SYNOPSIS: Running well and safely in the heat is challenging for all runners, from recreational to elite. As environmental heat stress (heat stress modulated or augmented by air temperature, humidity, wind speed, and solar radiation) and the intensity and duration of a training run or race increase, so are metabolic heat production, the parallel need for heat transfer from the body to maintain thermal equilibrium, the consequent increase in blood flow to the skin, and the concomitant sweating response progressively and proportionally amplified. An accumulating total body-water deficit from extensive sweating and escalating level of cardiovascular and thermal strain will, in due course, considerably challenge a runner's physiology, perception of effort, and on-course well-being and performance. However, with the appropriate preparation and modifications to planned running intensity and distance, runners can safely tolerate and effectively train and compete in a wide range of challenging environmental conditions. Clinicians play a key role in this regard as an effective resource for providing the most effective guidelines and making the best overall individual recommendations regarding training and competing in the heat. Copyright © 2014 Journal of Orthopaedic & Sports Physical Therapy. All rights reserved.


Miller J.N.,University of South Dakota | Miller J.N.,Sanford Childrens Health Research Center | Kovacs A.D.,Sanford Childrens Health Research Center | Pearce D.A.,University of South Dakota | Pearce D.A.,Sanford Childrens Health Research Center
Human Molecular Genetics | Year: 2015

The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of autosomal recessive neurodegenerative disorders in children characterized by the progressive onset of seizures, blindness, motor and cognitive decline and premature death. Patients with mutations in CLN1 primarily manifest with infantile NCL (INCL or Haltia-Santavuori disease), which is second only to congenital NCL for its age of onset and devastating progression. CLN1 encodes a lysosomal enzyme, palmitoyl-protein thioesterase 1 (PPT1). Nonsense mutations in CLN1 account for 52.3% of all disease causing alleles in infantile NCL, the most common of which worldwide is the p.R151X mutation. Previously, we have shown how nonsense-mediated decay is involved in the degradation of CLN1 mRNA transcripts containing the p.R151X mutation in human lymphoblast cell lines. We have also shown how the read-through drugs gentamicin and ataluren (PTC124) increase CLN1 (PPT1) enzyme activity. Here, we provide the initial characterization of the novel Cln1R151X mouse model of infantile neuronal ceroid lipofuscinosis that we have generated. This nonsense mutation model recapitulates the molecular, histological and behavioral phenotypes of the human disease. Cln1R151X mice showed a significant decrease in Cln1 mRNA level and PPT1 enzyme activity, accumulation of autofluorescent storage material, astrocytosis and microglial activation in the brain. Behavioral characterization of Cln1R151X mice at 3 and 5 months of age revealed significant motor deficits as measured by the vertical pole and rotarod tests. We also show how the read-through compound ataluren (PTC124) increases PPT1 enzyme activity and protein level in Cln1R151X mice in a proof-of-principle study. © The Author 2014. Published by Oxford University Press. All rights reserved.

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