Publications by authors named "Caleb P Bupp"

10 Publications

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SARS-CoV-2 infection: molecular mechanisms of severe outcomes to suggest therapeutics.

Expert Rev Proteomics 2021 Apr 5:1-14. Epub 2021 Apr 5.

Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.

The year 2020 was defined by the 29,903 base pairs of RNA that codes for the SARS-CoV-2 genome. SARS-CoV-2 infects humans to cause COVID-19, spreading from patient-to-patient yet impacts patients very divergently. Within this review, we address the known molecular mechanisms and supporting data for COVID-19 clinical course and pathology, clinical risk factors and molecular signatures, therapeutics of severe COVID-19, and reinfection/vaccination. Literature and published datasets were reviewed using PubMed, Google Scholar, and NCBI SRA tools. The combination of exaggerated cytokine signaling, pneumonia, NETosis, pyroptosis, thrombocytopathy, endotheliopathy, multiple organ dysfunction syndrome (MODS), and acute respiratory distress syndrome (ARDS) create a positive feedback loop of severe damage in patients with COVID-19 that impacts the entire body and may persist for months following infection. Understanding the molecular pathways of severe COVID-19 opens the door for novel therapeutic design. We summarize the current insights into pathology, risk factors, secondary infections, genetics, omics, and drugs being tested to treat severe COVID-19.: A growing level of support suggests the need for stronger integration of biomarkers and precision medicine to guide treatment strategies of severe COVID-19, where each patient has unique outcomes and thus require guided treatment.
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http://dx.doi.org/10.1080/14789450.2021.1908894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022340PMC
April 2021

Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior.

Genet Med 2021 Mar 3. Epub 2021 Mar 3.

Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.

Purpose: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis.

Methods: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes.

Results: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes.

Conclusion: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
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http://dx.doi.org/10.1038/s41436-021-01114-zDOI Listing
March 2021

Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder.

Genet Med 2021 Feb 11;23(2):384-395. Epub 2020 Nov 11.

Institute of Human Genetics, Technical University Munich, Munich, Germany.

Purpose: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome).

Methods: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers.

Results: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined.

Conclusion: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.
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http://dx.doi.org/10.1038/s41436-020-00993-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862064PMC
February 2021

Biochemical features of primary cells from a pediatric patient with a gain-of-function genetic mutation.

Biochem J 2019 07 24;476(14):2047-2057. Epub 2019 Jul 24.

Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, U.S.A.

We recently described a new autosomal dominant genetic disorder in a pediatric patient caused by a heterozygous mutation in the ornithine decarboxylase 1 () gene. The new genetic disorder is characterized by global developmental delay, alopecia, overgrowth, and dysmorphic features. We hypothesized that this new mutation (c.1342 A>T) leads to a C-terminal truncation variant of the ODC protein that is resistant to normal proteasomal degradation, leading to putrescine accumulation in cells. ODC (E.C. 4.1.1.17) is a rate-limiting enzyme in the biosynthesis of polyamines (putrescine, spermidine, and spermine) that plays a crucial role during embryogenesis, organogenesis, and tumorigenesis. In this study, we show that primary dermal fibroblasts derived from a skin biopsy of a 3-year-old patient contain large amounts of ODC protein and putrescine compared with primary dermal (neonatal and adult) fibroblast control cells. Importantly, the accumulated ODC protein variant remained functionally active as we detected exceptionally high ODC enzyme activity in both primary dermal fibroblasts (12-17-fold of controls) and red blood cells (RBCs) (125-137-fold of controls), using a specific C radioactive ODC activity assay. Exposure of primary dermal fibroblasts to ODC inhibitor α-difluoromethylornithine (DFMO) reduced the ODC activity and putrescine to levels observed in controls without adversely affecting cell morphology or inducing cell death. In conclusion, our patient and potentially other patients that carry a similar gain-of-function mutation might benefit from treatment with DFMO, a drug with a good safety profile, to suppress the exceptionally high ODC activity and putrescine levels in the body.
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http://dx.doi.org/10.1042/BCJ20190294DOI Listing
July 2019

Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.

Am J Med Genet A 2018 12 21;176(12):2548-2553. Epub 2018 Sep 21.

Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan.

The ornithine decarboxylase 1 (ODC1) gene plays an important role in physiological and cell developmental processes including embryogenesis, organogenesis, and neoplastic cell growth. Here, we report an 32-month-old Caucasian female with a heterozygous de novo nonsense mutation in the ODC1 gene that leads to a premature abrogation of 14-aa residues at the ODC protein c-terminus. This is the first human case confirming similar symptoms observed in a transgenic ODC1 mouse model first described over 20 years ago. Phenotypic manifestations include macrosomia, macrocephaly, developmental delay, alopecia, spasticity, hypotonia, cutaneous vascular malformation, delayed visual maturation, and sensorineural hearing loss. We here describe for the first time a new pediatric disorder that is directly linked to a de novo pathogenic variant in the ODC1 gene. The ODC1 gene mutation (c.1342 A>T) was identified by whole-exome sequencing and confirmed by Sanger sequencing. Red blood cells obtained from our patient showed elevated ODC protein and polyamine levels compared to healthy controls. Our autosomal dominant patient who carries this gain-of-function ODC1 mutation may benefit from treatment with α-difluoromethylornithine, a well-tolerated, U.S. Food and Drug Administration (FDA). FDA-approved drug.
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http://dx.doi.org/10.1002/ajmg.a.40523DOI Listing
December 2018

De novo missense variants in PPP1CB are associated with intellectual disability and congenital heart disease.

Hum Genet 2016 12 28;135(12):1399-1409. Epub 2016 Sep 28.

Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA.

Intellectual disabilities are genetically heterogeneous and can be associated with congenital anomalies. Using whole-exome sequencing (WES), we identified five different de novo missense variants in the protein phosphatase-1 catalytic subunit beta (PPP1CB) gene in eight unrelated individuals who share an overlapping phenotype of dysmorphic features, macrocephaly, developmental delay or intellectual disability (ID), congenital heart disease, short stature, and skeletal and connective tissue abnormalities. Protein phosphatase-1 (PP1) is a serine/threonine-specific protein phosphatase involved in the dephosphorylation of a variety of proteins. The PPP1CB gene encodes a PP1 subunit that regulates the level of protein phosphorylation. All five altered amino acids we observed are highly conserved among the PP1 subunit family, and all are predicted to disrupt PP1 subunit binding and impair dephosphorylation. Our data suggest that our heterozygous de novo PPP1CB pathogenic variants are associated with syndromic intellectual disability.
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http://dx.doi.org/10.1007/s00439-016-1731-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663278PMC
December 2016

When folic acid fails: Insights from 20 years of neural tube defect surveillance in South Carolina.

Am J Med Genet A 2015 Oct 24;167A(10):2244-50. Epub 2015 Jun 24.

Greenwood Genetic Center, Greenwood, South Carolina.

Neural tube defects (NTDs) are the most common of the severe malformations of the brain and spinal cord. Increased maternal intake of folic acid (FA) during the periconceptional period is known to reduce NTD risk. Data from 1046 NTD cases in South Carolina were gathered over 20 years of surveillance. It was possible to determine maternal periconceptional FA use in 615 NTD-affected pregnancies. In 163 occurrent (26.9%) and two recurrent (22%) NTD cases, the mothers reported periconceptional FA use. These women were older and more likely to be white. Maternal periconceptional FA usage was reported in 40.4% of cases of spina bifida with other anomalies but in only 25.2% of isolated spina bifida cases (P = 0.02). This enrichment for associated anomalies was not noted among cases of anencephaly or of encephalocele. Among the 563 subsequent pregnancies to mothers with previous NTD-affected pregnancies, those taking FA had a 0.4% NTD recurrence rate, but the recurrence without FA was 8.5%. NTDs with other associated findings were less likely to be prevented by FA, suggesting there is a background NTD rate that cannot be further reduced by FA. Nonetheless, the majority (73.9%) of NTDs in pregnancies in which the mothers reported periconceptional FA use were isolated NTDs of usual types. Cases in which FA failed in prevention of NTDs provide potential areas for further study into the causation of NTDs. The measures and techniques implemented in South Carolina can serve as an effective and successful model for prevention of NTD occurrence and recurrence.
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http://dx.doi.org/10.1002/ajmg.a.37168DOI Listing
October 2015

Surveying the current landscape of clinical genetics residency training.

Genet Med 2015 May 18;17(5):386-90. Epub 2014 Sep 18.

Children's Hospital, Greenville Health System, Greenville, South Carolina, USA.

Purpose: Further knowledge about medical genetics residency training structure and function could help advance this educational process.

Methods: Medical genetics residency program directors were surveyed about their trainees' backgrounds and skills as well as the recruitment and matching process.

Results: Previous resident training was predominantly in pediatrics (49%). Average ratings of residents' beginning clinical knowledge (scale of 1-10, minimal to superior) were: dysmorphology - 3.5, inborn errors of metabolism - 2.5, prenatal genetics - 2.6, and cancer genetics - 2.8. On average, four months of research were required for categorical residency and fifteen months for combined residency. For the 2011 transition to ERAS/NRMP, 69% of program directors were extremely or somewhat prepared; however, 21% felt unprepared. The number of trainees at most institutions remained unchanged. 36% of respondents reported that ERAS/NRMP has had no impact on recruitment of trainees, and 26% felt it has had a slightly positive impact. Continued utilization was recommended by 71% while 5% disagreed.

Conclusion: Genetics residents come from diverse training backgrounds. Their education can be directed toward specific areas of perceived initial weakness. ERAS/NRMP has not drastically increased entrance into the field. Further discussions are merited regarding enhancement of medical genetics residency recruitment and training.
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http://dx.doi.org/10.1038/gim.2014.108DOI Listing
May 2015

Truncating mutations in LRP4 lead to a prenatal lethal form of Cenani-Lenz syndrome.

Am J Med Genet A 2014 Sep 12;164A(9):2391-7. Epub 2014 Jun 12.

Greenwood Genetic Center, Greenwood, South Carolina.

Cenani-Lenz syndrome (CLS) is an autosomal recessive skeletal dysplasia that results in malformations of the distal limb, renal anomalies, and characteristic facies. In 2010, this condition was found to be caused by mutations in LRP4, a member of the low-density lipoprotein family of receptors. LRP4 has been shown to antagonize LRP5/LRP6 activation of WNT and β-catenin signaling. Loss of LRP4 function leads to excessive Wnt and β-catenin signaling in the limb bud, which causes abnormal limb development. The large majority of patients with CLS reported in the literature have splicing and missense mutations, which result in syndactyly, oligodactyly, and minor renal malformations. More recently, a patient with CLS has been identified with a homozygous nonsense mutation and a more severe presentation of findings typically associated with this condition. Here we present two sibling fetuses with a prenatal lethal presentation of mesomelic limb reductions, oligosyndactyly, genitourinary malformation and compound heterozygosity for two novel truncating mutations in LRP4. These findings lend further support to the CLS genotype-phenotype correlation presented in recent publications.
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http://dx.doi.org/10.1002/ajmg.a.36647DOI Listing
September 2014