Publications by authors named "Chris D Balak"

4 Publications

  • Page 1 of 1

Compound heterozygous mutations in SNAP29 is associated with Pelizaeus-Merzbacher-like disorder (PMLD).

Hum Genet 2019 Dec 20;138(11-12):1409-1417. Epub 2019 Nov 20.

Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ, USA.

Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating leukodystrophy, which is clinically and radiologically similar to X-linked Pelizaeus-Merzbacher disease (PMD). PMLD is characterized by early-onset nystagmus, delayed development (motor delay, speech delay and dysarthria), dystonia, hypotonia typically evolving into spasticity, ataxia, seizures, optic atrophy, and diffuse leukodystrophy on magnetic resonance imaging (MRI). We identified a 12-year-old Caucasian/Hispanic male with the classical clinical characteristics of PMLD with lack of myelination of the subcortical white matter, and absence of the splenium of corpus callosum. Exome sequencing in the trio revealed novel compound heterozygous pathogenic mutations in SNAP29 (p.Leu119AlafsX15, c.354DupG and p.0?, c.2T > C). Quantitative analysis of the patient's blood cells through RNA sequencing identified a significant decrease in SNAP29 mRNA expression, while western blot analysis on fibroblast cells revealed a lack of protein expression compared to parental and control cells. Mutations in SNAP29 have previously been associated with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome. Typical skin features described in CEDNIK syndrome, such as generalized ichthyosis and keratoderma, were absent in our patient. Moreover, the early onset nystagmus and leukodystrophy were consistent with a PMLD diagnosis. These findings suggest that loss of SNAP29 function, which was previously associated with CEDNIK syndrome, is also associated with PMLD. Overall, our study expands the genetic spectrum of PMLD.
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http://dx.doi.org/10.1007/s00439-019-02077-7DOI Listing
December 2019

Associations of Gene Variants With Superior Memory in SuperAgers.

Front Aging Neurosci 2018 29;10:155. Epub 2018 May 29.

Cognitive Neurology & Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine (NU FSM), Chicago, IL, United States.

: SuperAgers are adults age 80+ with episodic memory performance that is as good as that of average middle-aged adults. Understanding the biological determinants of SuperAging may have relevance to preventing age-related cognitive decline and dementia. This study aimed to identify associations between genetic variations and the SuperAging phenotype using Whole Exome Sequencing (WES). : Sequence Kernel Association Combined (SKAT-C) test was conducted at the gene level including both rare and common variants in 56 SuperAgers and 22 cognitively-average controls from the Alzheimer's disease Neuroimaging Initiative (ADNI). : The SuperAging phenotype was associated with variants in the Mitogen-Activated Protein Kinase Kinase 3 gene. Three single nucleotide polymorphisms (SNPs) contributed to the significance (rs2363221 [intron 1], rs2230435 [exon 5], rs736103 [intron 7]). : MAP2K3 resides in a biological pathway linked to memory. It is in a signaling cascade associated with beta-amyloid mediated apoptosis and has enriched expression in microglia. This preliminary work suggests MAP2K3 may represent a novel therapeutic target for age-related memory decline and perhaps Alzheimer's disease (AD).
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http://dx.doi.org/10.3389/fnagi.2018.00155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987172PMC
May 2018

Functional characterizations of rare variants in X-linked Spinal Muscular Atrophy.

F1000Res 2017 4;6:1636. Epub 2017 Sep 4.

Translational Genomics Research Institute (TGen), Phoenix, Arizona, 85004, USA.

X-linked spinal muscular atrophy (XL-SMA) results from mutations in the Ubiquitin-Like Modifier Activating Enzyme 1 ( ). Previously, four novel closely clustered mutations have been shown to cause this fatal infantile disorder affecting only males. These mutations, three missense and one synonymous, all lie within Exon15 of the gene, which contains the active adenylation domain (AAD). In this study, our group characterized the three known missense variants . Using a novel Uba1 assay and other methods, we investigated Uba1 adenylation, thioester, and transthioesterification reactions to determine possible biochemical effects of the missense variants. Our data revealed that only one of the three XL-SMA missense variants impairs the Ubiquitin-adenylating ability of Uba1. Additionally, these missense variants retained Ubiquitin thioester bond formation and transthioesterification rates equal to that found in the wild type. Our results demonstrate a surprising shift from the likelihood of these XL-SMA mutations playing a damaging role in Uba1's enzymatic activity with Ubiquitin, to other roles such as altering  mRNA splicing via the disruption of splicing factor binding sites, similar to a mechanism in traditional SMA, or disrupting binding to other important binding partners.  These findings help to narrow the search for the areas of possible dysfunction in the Ubiquitin-proteasome pathway that ultimately result in XL-SMA. Moreover, this investigation provides additional critical understanding of the mutations' biochemical mechanisms, vital for the development of future effective diagnostic assays and therapeutics.
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http://dx.doi.org/10.12688/f1000research.11878.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5615770PMC
September 2017

Exploring genome-wide DNA methylation patterns in Aicardi syndrome.

Epigenomics 2017 11 2;9(11):1373-1386. Epub 2017 Oct 2.

Center for Rare Childhood Disorders, Translational Genomics Research Institute, 445 N 5th Street, Phoenix, AZ, USA.

Aim: To explore differential DNA methylation (DNAm) in Aicardi syndrome (AIC), a severe neurodevelopmental disorder with largely unknown etiology.

Patients & Methods: We characterized DNAm in AIC female patients and parents using the Illumina 450 K array. Differential DNAm was assessed using the local outlier factor algorithm, and results were validated via qPCR in a larger set of AIC female patients, parents and unrelated young female controls. Functional epigenetic modules analysis was used to detect pathways integrating both genome-wide DNAm and RNA-seq data.

Results & Conclusion: We detected differential methylation patterns in AIC patients in several neurodevelopmental and/or neuroimmunological networks. These networks may be part of the underlying pathogenic mechanisms involved in the disease.
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http://dx.doi.org/10.2217/epi-2017-0060DOI Listing
November 2017