A5056941176- Genetics and Neurodevelopmental Disorders
- Cellular transport and secretion
- RNA regulation and disease
- Blood Coagulation and Thrombosis Mechanisms
- Genetic Syndromes and Imprinting
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Hemophilia Treatment and Research
- Genomics and Rare Diseases
- CRISPR and Genetic Engineering
- Retinal Development and Disorders
- Lysosomal Storage Disorders Research
- Cancer Treatment and Pharmacology
- Epigenetics and DNA Methylation
- Urticaria and Related Conditions
- Physics and Engineering Research Articles
- Amino Acid Enzymes and Metabolism
- Lipid Membrane Structure and Behavior
- Neurogenetic and Muscular Disorders Research
- Drug-Induced Adverse Reactions
- Glycogen Storage Diseases and Myoclonus
- Phytochemistry and Bioactive Compounds
- Genomic variations and chromosomal abnormalities
- Metabolism and Genetic Disorders
- Fibroblast Growth Factor Research
- Venous Thromboembolism Diagnosis and Management
Brown University
2011-2024
Allen Institute for Brain Science
2019-2023
Providence College
2013-2023
Bradley Hospital
2016-2022
Institute of Molecular and Cell Biology
2022
John Brown University
2017-2021
Universitätsklinikum Erlangen
2016
Friedrich-Alexander-Universität Erlangen-Nürnberg
2016
Dr. John T. Macdonald Foundation
2013
University of Miami
2013
Objective Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X‐linked Na + /H exchanger 6 ( NHE6 ). We aimed determine diagnostic criteria and mutational spectrum for CS. Methods Twelve independent pedigrees (14 boys, age = 4–19 years) with were administered standardized research assessments, characterized. Results The was composed of 9 single nucleotide variants, 2 indels, 1 copy number variation deletion. All protein‐truncating or splicing mutations....
Significance We report autosomal recessive mutations in the enzyme glutamate pyruvate transaminase 2 (GPT2) a neurological syndrome involving intellectual disability, reduced brain growth, and progressive motor symptoms. show that inactivate enzyme. GPT2 catalyzes reversible addition of an amino group from to pyruvate, yielding alanine α-ketoglutarate. The gene demonstrates expression postnatally, protein localizes mitochondria. As humans, Gpt2 -null mice exhibit growth. Furthermore, mutant...
Neurons from patient-derived iPSCs demonstrate mutation-specific responses to potential therapeutic strategies for Christianson syndrome.
Autism spectrum disorder (ASD) affects 1 in 44 children. Chromatin regulatory proteins are overrepresented among genes that contain high risk variants ASD. Disruption of the chromatin environment leads to widespread dysregulation gene expression, which is traditionally thought as a mechanism disease pathogenesis associated with Alternatively, alterations dynamics could also lead alternative splicing, understudied ASD pathogenesis. The anticonvulsant valproic acid (VPA) well-known...
Activated recombinant human coagulation factor VII (rFVIIa) is a promising new therapeutic agent for patients with hemophilia A or B inhibitors who experience serious bleeding episodes need coverage during surgical procedures. This open-label, uncontrolled, emergency-use study evaluated the efficacy and safety of rFVIIa in 11 hemophiliac 1 FVII-deficient patient life-threatening intracranial hemorrhage previously unresponsive to one more alternative therapies. effectively controlled 10 12...
Loss-of-function mutations in the X-linked endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome males. involves endosome dysfunction leading to early cerebellar degeneration, as well later-onset cortical and subcortical neurodegeneration, potentially including tau deposition reported post-mortem studies. In addition, there is evidence of modulation amyloid-β levels experimental models wherein NHE6 expression was targeted. We have recently shown that loss causes defects maturation...
We report the use of recombinant VIIa (rFVIIa) in treatment five ICHs two factor VIII-deficient patients with inhibitors. In four ICHs, rFVIIa was only replacement used at doses 60-135 micrograms/kg every 2-4 hr for 12-14 days. Hemostasis primary site bleeding achieved all cases, and survived no permanent neurologic deficits. However, patient who received highest dose during first 4 days therapy developed clinical symptoms consistent a cerebral vascular accident brainstem characterized by...
Activity-dependent neuroprotective protein (ADNP) is a highly conserved transcription factor comprised of nine-zinc finger domains and homeobox domain.1 ,2 It expressed prenatally during critical stages embryonic brain development.3 Knockout (KO) mouse embryos demonstrate severe neurodevelopmental morphological profiles.4 Although the ADNP KO lethal, heterozygous typical embryogenesis yet display delay phenotype including decreased neuronal survival.3 ,5 Exome sequencing in Simons Simplex...
Abstract Christianson syndrome (CS) is an X-linked disorder resulting from loss-of-function mutations in SLC9A6 , which encodes the endosomal Na + /H exchanger 6 (NHE6). Symptoms include early developmental delay, seizures, intellectual disability, nonverbal status, autistic features, postnatal microcephaly, and progressive ataxia. Neuronal development impaired CS, involving defects neuronal arborization synaptogenesis, likely underlying diminished brain growth postnatally. In addition to...
Aspartate-glutamate carrier 1 (AGC1) is one of two exchangers within the malate-aspartate shuttle. AGC1 encoded by SLC25A12 gene. Three patients with pathogenic variants in have been reported literature. These were clinically characterized neurodevelopmental delay, epilepsy, hypotonia, cerebral atrophy, and hypomyelination; however, there has discussion literature as to whether this hypomyelination primary or secondary a neuronal defect. Here we report 12-year-old patient magnetic resonance...
Mutations in <i>NHE6</i> (also termed <i>SLC9A6</i>) cause the X-linked neurological disorder Christianson syndrome (CS) males. The purpose of this study was to examine phenotypic spectrum female carriers mutations. Twenty from 9 pedigrees were enrolled, ranging approximately age 2 65. A subset assessed using standardized neuropsychological measures. Also, association expression with markers brain evaluated 740 participants Religious Orders Study (ROS) and Rush Memory...
Abstract Background Pathway analysis based on Genome-Wide Association Studies (GWAS) data has become popular as a secondary strategy. Although many pathway tools have been developed for case-control studies, there is no tool that can use all information from raw genotypes in general nuclear families. We Pathway-PDT, which uses the framework of Pedigree Disequilibrium Test (PDT) family data, to perform family-based GWAS. Results Simulation results showed Pathway-PDT more powerful than p-value...
Abstract Christianson syndrome (CS) is an X-linked neurogenetic disorder resulting from loss-of-function (LoF) mutations in SLC9A6 , which encodes the endosomal Na + /H exchanger 6 (NHE6). NHE6 regulates proton efflux endosomes and, thus, participates regulating cargo processing and trafficking. LoF cause aberrant acidification of endosomes. While CS arises males generally due to clear mutations, other potentially hypomorphic variants have emerged, yet most these not been evaluated for...
Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is an autosomal recessive neurodegenerative disorder generally with onset at to 4 years of age and characterized by seizures, loss vision, progressive motor mental decline, premature death. CLN2 disease caused loss-of-function mutations in the tripeptidyl peptidase 1 (TPP1) gene leading deficiency TPP1 enzyme activity. Approximately 60% patients have one two pathogenic variants (c.509-1G > C or c.622C T [p.(Arg208*)]). In order generate a...
In 2000, Gardner and Collins reported the construction of a fundamental genetic regulatory device, bi-stable toggle switch, in E. coli. We report here our work on natural extension this powerful tri-stable switch capable switching among three stable states. Like consists repressible promoters that produce inhibitory proteins requires only transient pulse chemical inducer to Our proof-of-principal construct is designed control expression different fluorescent reporters using pBad/AraC,...
Loss-of-function mutations in Na+/H + exchanger 6 (NHE6) (also termed SLC9A6) cause the X-linked neurogenetic disorder Christianson syndrome (CS). Using peripheral blood mononuclear cells, we developed induced pluripotent stem cell (iPSC) lines from a patient with NHE6 nonsense mutation c.1569G > A (p.(W523X)) and diagnosed CS biologically-related control. CRISPR/Cas9 gene editing, generated two isogenic control which was corrected. All were verified by DNA sequencing for protein expression,...
Mutations in the endosomal Na+/H+ exchanger 6 (NHE6) cause Christianson syndrome, an X-linked neurological disorder. NHE6 functions regulation of endosome acidification and maturation neurons. Using yeast two-hybrid screening with carboxyl terminus as bait, we identify Golgi-associated, gamma adaptin ear-containing, ADP-ribosylation factor (ARF) binding protein 1 (GGA1) interacting partner for NHE6. We corroborated NHE6-GGA1 interaction using: coimmunoprecipitation; overexpressed constructs...