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1. Long QT syndrome-associated mutations in intrauterine fetal death.

Author

Crotti, L, Tester, D, White, M, Bartos, D, Insolia, R, Besana, A, Kunic, J, Will, M, Velasco, E, Bair, J, Ghidoni, A, Cetin, I, Van Dyke, D, Wick, M, Brost, B, Delise, B, Facchinetti, F, George, A, Schwartz, P, Ackerman, M, Tester, DJT, White, MW, Bartos, DC, Kunic, JD, Will, ML, Velasco, EJ, Bair, JJ, Van Dyke, DL, Wick, MJ, Delise, BP, George, AL, Schwartz, PJ, Ackerman, MJ., Crotti, L, Tester, D, White, M, Bartos, D, Insolia, R, Besana, A, Kunic, J, Will, M, Velasco, E, Bair, J, Ghidoni, A, Cetin, I, Van Dyke, D, Wick, M, Brost, B, Delise, B, Facchinetti, F, George, A, Schwartz, P, Ackerman, M, Tester, DJT, White, MW, Bartos, DC, Kunic, JD, Will, ML, Velasco, EJ, Bair, JJ, Van Dyke, DL, Wick, MJ, Delise, BP, George, AL, Schwartz, PJ, and Ackerman, MJ.

Abstract

Importance: Intrauterine fetal death or stillbirth occurs in approximately 1 out of every 160 pregnancies and accounts for 50% of all perinatal deaths. Postmortem evaluation fails to elucidate an underlying cause in many cases. Long QT syndrome (LQTS) may contribute to this problem. Objective: To determine the spectrum and prevalence of mutations in the 3 most common LQTS susceptible genes (KCNQ1, KCNH2, and SCN5A) for a cohort of unexplained cases. Design, Setting, and Patients: In this case series, retrospective postmortem genetic testing was conducted on a convenience sample of 91 unexplained intrauterine fetal deaths (mean [SD] estimated gestational age at fetal death, 26.3 [8.7] weeks) that were collected from 2006-2012 by the Mayo Clinic, Rochester, Minnesota, or the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. More than 1300 ostensibly healthy individuals served as controls. In addition, publicly available exome databases were assessed for the general population frequency of identified genetic variants. Main Outcomes and Measures: Comprehensive mutational analyses of KCNQ1 (KV7.1, LQTS type 1), KCNH2 (HERG/KV11.1, LQTS type 2), and SCN5A (NaV1.5, LQTS type 3) were performed using denaturing high-performance liquid chromatography and direct DNA sequencing on genomic DNA extracted from decedent tissue. Functional analyses of novel mutations were performed using heterologous expression and patch-clamp recording. Results: The 3 putative LQTS susceptibility missense mutations (KCNQ1, p.A283T; KCNQ1, p.R397W; and KCNH2[1b], p.R25W), with a heterozygous frequency of less than 0.05% in more than 10 000 publicly available exomes and absent in more than 1000 ethnically similar control patients, were discovered in 3 intrauterine fetal deaths (3.3% [95% CI, 0.68%-9.3%]). Both K V7.1-A283T (16-week male) and KV7.1-R397W (16-week female) mutations were associated with marked KV7.1 loss-of-function consistent with in utero LQTS type 1, whereas the HERG1b-R25W muta

Published
2013

2. Calmodulin mutations associated with recurrent cardiac arrest in infants

Author

Crotti, L, Johnson, C, Graf, E, De Ferrari, G, Cuneo, B, Ovadia, M, Papagiannis, J, Feldkamp, M, Rathi, S, Kunic, J, Pedrazzini, M, Wieland, T, Lichtner, P, Beckmann, B, Clark, T, Shaffer, C, Benson, D, Kääb, S, Meitinger, T, Strom, T, Chazin, W, Schwartz, P, George AL, J, Crotti L., Johnson CN., Graf E., De Ferrari G., Cuneo BF., Ovadia M., Papagiannis J., Feldkamp MD., Rathi SG., Kunic JD., Pedrazzini M., Wieland T., Lichtner P., Beckmann BM., Clark T., Shaffer C., Benson DW., Kääb S., Meitinger T., Strom TM., Chazin WJ., Schwartz P, George AL Jr., Crotti, L, Johnson, C, Graf, E, De Ferrari, G, Cuneo, B, Ovadia, M, Papagiannis, J, Feldkamp, M, Rathi, S, Kunic, J, Pedrazzini, M, Wieland, T, Lichtner, P, Beckmann, B, Clark, T, Shaffer, C, Benson, D, Kääb, S, Meitinger, T, Strom, T, Chazin, W, Schwartz, P, George AL, J, Crotti L., Johnson CN., Graf E., De Ferrari G., Cuneo BF., Ovadia M., Papagiannis J., Feldkamp MD., Rathi SG., Kunic JD., Pedrazzini M., Wieland T., Lichtner P., Beckmann BM., Clark T., Shaffer C., Benson DW., Kääb S., Meitinger T., Strom TM., Chazin WJ., Schwartz P, and George AL Jr.

Abstract

Background-: Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on 2 unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause. Methods and Results-: We ascertained 2 unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents. The 2 parent-child trios were investigated with the use of exome sequencing to search for de novo genetic variants. We then performed follow-up candidate gene screening on an independent cohort of 82 subjects with congenital long-QT syndrome without an identified genetic cause. Biochemical studies were performed to determine the functional consequences of mutations discovered in 2 genes encoding calmodulin. We discovered 3 heterozygous de novo mutations in either CALM1 or CALM2, 2 of the 3 human genes encoding calmodulin, in the 2 probands and in 2 additional subjects with recurrent cardiac arrest. All mutation carriers were infants who exhibited life-threatening ventricular arrhythmias combined variably with epilepsy and delayed neurodevelopment. Mutations altered residues in or adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain. Recombinant mutant calmodulins exhibited several-fold reductions in calcium binding affinity. Conclusions-: Human calmodulin mutations disrupt calcium ion binding to the protein and are associated with a life-threatening condition in early infancy. Defects in calmodulin function will disrupt important calcium signaling events in heart, affecting membrane ion channels, a plausible molecular mechanism for potentially deadly disturbances in heart rhythm during infancy

Published
2013

3. Statins and fenofibrate affect skeletal muscle chloride conductance in rats by differently impairing ClC-1 channel regulation and expression.

Author

Pierno, S., Camerino, G. M., Cippone, V., Rolland, J.-F., Desaphy, J.-F., De Luca, A., Liantonio, A., Bianco, G., Kunic, J. D., George, Jr., A. L., Camerino, D. Conte, George, A L Jr, and Conte Camerino, D

Subjects
ANTILIPEMIC agents, STATINS (Cardiovascular agents), CELLULAR mechanics, MESSENGER RNA, EFFECT of drugs on cells, POLYMERASE chain reaction
Abstract

Background and Purpose: Statins and fibrates can produce mild to life-threatening skeletal muscle damage. Resting chloride channel conductance (gCl), carried by the ClC-1 channel, is reduced in muscles of rats chronically treated with fluvastatin, atorvastatin or fenofibrate, along with increased resting cytosolic calcium in statin-treated rats. A high gCl, controlled by the Ca(2+)-dependent protein kinase C (PKC), maintains sarcolemma electrical stability and its reduction alters muscle function. Here, we investigated how statins and fenofibrate impaired gCl.Experimental Approach: In rats treated with fluvastatin, atorvastatin or fenofibrate, we examined the involvement of PKC in gCl reduction by the two intracellular microelectrodes technique and ClC-1 mRNA level by quantitative real time-polymerase chain reaction. Direct drug effects were tested by patch clamp analysis on human ClC-1 channels expressed in human embryonic kidney (HEK) 293 cells.Key Results: Chelerythrine, a PKC inhibitor, applied in vitro on muscle dissected from atorvastatin-treated rats fully restored gCl, suggesting the involvement of this enzyme in statin action. Chelerythrine partially restored gCl in muscles from fluvastatin-treated rats but not in those from fenofibrate-treated rats, implying additional mechanisms for gCl impairment. Accordingly, a decrease of ClC-1 channel mRNA was found in both fluvastatin- and fenofibrate-treated rat muscles. Fenofibric acid, the in vivo metabolite of fenofibrate, but not fluvastatin, rapidly reduced chloride currents in HEK 293 cells.Conclusions and Implications: Our data suggest multiple mechanisms underlie the effect of statins and fenofibrate on ClC-1 channel conductance. While statins promote Ca(2+)-mediated PKC activation, fenofibrate directly inhibits ClC-1 channels and both fluvastatin and fenofibrate impair expression of mRNA for ClC-1. [ABSTRACT FROM AUTHOR]

Published
2009
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4. Long QT Syndrome–Associated Mutations in Intrauterine Fetal Death

Author

Brian P. Delisle, Daniel C. Bartos, Lia Crotti, Fabio Facchinetti, Alice Ghidoni, Alfred L. George, Alessandra Besana, Melissa L. Will, Wendy M. White, Michael J. Ackerman, Peter J. Schwartz, Daniel L. Van Dyke, Irene Cetin, Jennifer J. Bair, Roberto Insolia, Ellyn J. Velasco, Brian C. Brost, Myra J. Wick, Jennifer D. Kunic, David J. Tester, Crotti, L, Tester, D, White, M, Bartos, D, Insolia, R, Besana, A, Kunic, J, Will, M, Velasco, E, Bair, J, Ghidoni, A, Cetin, I, Van Dyke, D, Wick, M, Brost, B, Delise, B, Facchinetti, F, George, A, Schwartz, P, and Ackerman, M

Subjects
Male, Pediatrics, ERG1 Potassium Channel, Autopsy, DNA Mutational Analysis, Ether-A-Go-Go Potassium Channels, genetics/metabolism, Female, Fetal Death, genetics, Fetus, physiopathology, Gene Expression, Humans, Infant, Newborn, KCNQ1 Potassium Channel, genetics/metabolism, Long QT Syndrome, genetics, Male, Mutation, Missense, Myocardium, metabolism, NAV1.5 Voltage-Gated Sodium Channel, genetics/metabolism, Retrospective Studies, DNA Mutational Analysis, genetics/metabolism, Gene Expression, Autopsy, Sudden cardiac death, NAV1.5 Voltage-Gated Sodium Channel, genetics, education.field_of_study, General Medicine, Fetal Presentation, Long QT Syndrome, KCNQ1 Potassium Channel, Female, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Long QT syndrome, Population, Mutation, Missense, BIO/18 - GENETICA, Sudden death, QT interval, Article, Fetus, Internal medicine, medicine, Humans, education, Fetal Death, Retrospective Studies, business.industry, Myocardium, Infant, Newborn, Infant, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, Sudden infant death syndrome, medicine.disease, Newborn, long QT syndrome, intrauterine fetal death, genetics, mutation, Ether-A-Go-Go Potassium Channels, Endocrinology, Mutation, physiopathology, Missense, business, metabolism
Abstract

IMPORTANCE: Intrauterine fetal death or stillbirth occurs in approximately 1 out of every 160 pregnancies and accounts for 50% of all perinatal deaths. Postmortem evaluation fails to elucidate an underlying cause in many cases. Long QT syndrome (LQTS) may contribute to this problem. OBJECTIVE: To determine the spectrum and prevalence of mutations in the 3 most common LQTS susceptible genes (KCNQ1, KCNH2, and SCN5A) for a cohort of unexplained cases. DESIGN, SETTING, AND PATIENTS: In this case series, retrospective postmortem genetic testing was conducted on a convenience sample of 91 unexplained intrauterine fetal deaths (mean [SD] estimated gestational age at fetal death, 26.3 [8.7] weeks) that were collected from 2006-2012 by the Mayo Clinic, Rochester, Minnesota, or the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. More than 1300 ostensibly healthy individuals served as controls. In addition, publicly available exome databases were assessed for the general population frequency of identified genetic variants. MAIN OUTCOMES AND MEASURES: Comprehensive mutational analyses of KCNQ1 (KV7.1, LQTS type 1), KCNH2 (HERG/KV11.1, LQTS type 2), and SCN5A (NaV1.5, LQTS type 3) were performed using denaturing high-performance liquid chromatography and direct DNA sequencing on genomic DNA extracted from decedent tissue. Functional analyses of novel mutations were performed using heterologous expression and patch-clamp recording. RESULTS: The 3 putative LQTS susceptibility missense mutations (KCNQ1, p.A283T; KCNQ1, p.R397W; and KCNH2 [1b], p.R25W), with a heterozygous frequency of less than 0.05% in more than 10 000 publicly available exomes and absent in more than 1000 ethnically similar control patients, were discovered in 3 intrauterine fetal deaths (3.3% [95% CI, 0.68%-9.3%]). Both KV7.1-A283T (16-week male) and KV7.1-R397W (16-week female) mutations were associated with marked KV7.1 loss-of-function consistent with in utero LQTS type 1, whereas the HERG1b-R25W mutation (33.2-week male) exhibited a loss of function consistent with in utero LQTS type 2. In addition, 5 intrauterine fetal deaths hosted SCN5A rare nonsynonymous genetic variants (p.T220I, p.R1193Q, involving 2 cases, and p.P2006A, involving 2 cases) that conferred in vitro electrophysiological characteristics consistent with potentially proarrhythmic phenotypes. CONCLUSIONS AND RELEVANCE: In this molecular genetic evaluation of 91 cases of intrauterine fetal death, missense mutations associated with LQTS susceptibility were discovered in 3 cases (3.3%) and overall, genetic variants leading to dysfunctional LQTS-associated ion channels in vitro were discovered in 8 cases (8.8%). These preliminary findings may provide insights into mechanisms of some cases of stillbirth.

Published
2013

5. Calmodulin mutations associated with recurrent cardiac arrest in infants

Author

Peter J. Schwartz, Travis Clark, Christopher N. Johnson, Tim M. Strom, Christian M. Shaffer, Thomas Meitinger, Subodh Rathi, D. Woodrow Benson, Gaetano M. De Ferrari, John Papagiannis, Elisabeth Graf, Michael D. Feldkamp, Britt M. Beckmann, Thomas Wieland, Marc Ovadia, Alfred L. George, Jennifer D. Kunic, Lia Crotti, Peter Lichtner, Matteo Pedrazzini, Walter J. Chazin, Stefan Kääb, Bettina F. Cuneo, Crotti, L, Johnson, C, Graf, E, De Ferrari, G, Cuneo, B, Ovadia, M, Papagiannis, J, Feldkamp, M, Rathi, S, Kunic, J, Pedrazzini, M, Wieland, T, Lichtner, P, Beckmann, B, Clark, T, Shaffer, C, Benson, D, Kääb, S, Meitinger, T, Strom, T, Chazin, W, Schwartz, P, and George AL, J

Subjects
Proband, Male, Candidate gene, 030204 cardiovascular system & hematology, Bioinformatics, medicine.disease_cause, Cohort Studies, 0302 clinical medicine, Arrhythmia, Calcium Signaling, Death, Sudden, Cardiac, Exome, Recurrence, Medicine, Exome sequencing, Genetics, 0303 health sciences, Mutation, 3. Good health, Pedigree, Long QT Syndrome, Child, Preschool, Cohort, Female, Cardiology and Cardiovascular Medicine, arrhythmia, calcium signaling, death, sudden, cardiac, exome, Long QT syndrome, Molecular Sequence Data, BIO/18 - GENETICA, 03 medical and health sciences, Calmodulin, Physiology (medical), Humans, Amino Acid Sequence, Gene, Genetic Association Studies, 030304 developmental biology, business.industry, Infant, Newborn, Infant, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, medicine.disease, Heart Arrest, business, Follow-Up Studies
Abstract

Background— Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on 2 unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause. Methods and Results— We ascertained 2 unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents. The 2 parent-child trios were investigated with the use of exome sequencing to search for de novo genetic variants. We then performed follow-up candidate gene screening on an independent cohort of 82 subjects with congenital long-QT syndrome without an identified genetic cause. Biochemical studies were performed to determine the functional consequences of mutations discovered in 2 genes encoding calmodulin. We discovered 3 heterozygous de novo mutations in either CALM1 or CALM2 , 2 of the 3 human genes encoding calmodulin, in the 2 probands and in 2 additional subjects with recurrent cardiac arrest. All mutation carriers were infants who exhibited life-threatening ventricular arrhythmias combined variably with epilepsy and delayed neurodevelopment. Mutations altered residues in or adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain. Recombinant mutant calmodulins exhibited several-fold reductions in calcium binding affinity. Conclusions— Human calmodulin mutations disrupt calcium ion binding to the protein and are associated with a life-threatening condition in early infancy. Defects in calmodulin function will disrupt important calcium signaling events in heart, affecting membrane ion channels, a plausible molecular mechanism for potentially deadly disturbances in heart rhythm during infancy.

Published
2013

6. Risk factors associated with Toxoplasma gondii seroprevalence in domestic pig farms in Argentina.

Author

Kunic JM, Bernstein M, Venturini MC, Pardini L, and Sommerfelt IE

Subjects
Animals, Antibodies, Protozoan, Argentina epidemiology, Farms, Risk Factors, Seroepidemiologic Studies, Sus scrofa, Swine, Swine Diseases epidemiology, Swine Diseases parasitology, Toxoplasma, Toxoplasmosis, Animal epidemiology, Toxoplasmosis, Animal parasitology
Abstract

Toxoplasmosis is a worldwide parasitic zoonosis caused by Toxoplasma gondii. Pigs can become infected by consuming water or food contaminated with sporulated oocysts, or by carnivorism (like the consumption of infected rodents). In pigs most infections are asymptomatic. In certain countries, pig meat containing tissue cysts is a major source of infection for human beings. The aims of this study were to estimate the seroprevalence of toxoplasmosis and to identify which factors were related with the increase of the risk of infection in Argentina. The seroprevalence of T. gondii was determined in 240 pigs from 27 farms in the central-western area of Buenos Aires province, Argentina. Serum samples were analyzed using indirect fluorescent antibody test (IFAT) and enzyme-linked immunosorbent assay (ELISA) techniques. Prevalence determined was 53.33% and 32.08% by IFAT and ELISA, respectively. Results showed that 81.5% (22/27) of the farms were seropositive to T. gondii. Seropositivity for T. gondii was related with the following risk factors (p value ≤0.05): presence of felids and rodents in the farms, feeding with waste of human food and storage of food outdoors with free access to felids and to the reservoirs when applying both serological techniques. Our results strongly suggest that the risk of infection with T. gondii in pigs is related to the outdoor/extensive type of production system with low infrastructure conditions, which allows both felids and rodents to have free access to pigs and stored food. Also, the high seroprevalence detected in the present study could indicate a potential role of pork in human infections in the region., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Published
2022
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7. Yip1B isoform is localized at ER-Golgi intermediate and cis-Golgi compartments and is not required for maintenance of the Golgi structure in skeletal muscle.

Author

Barone V, Mazzoli E, Kunic J, Rossi D, Tronnolone S, and Sorrentino V

Subjects
Animals, Cells, Cultured, Endoplasmic Reticulum metabolism, Golgi Apparatus metabolism, Mice, Muscle, Skeletal metabolism, Protein Isoforms analysis, Protein Isoforms biosynthesis, Protein Isoforms metabolism, Vesicular Transport Proteins biosynthesis, Endoplasmic Reticulum chemistry, Golgi Apparatus chemistry, Muscle, Skeletal chemistry, Vesicular Transport Proteins analysis, Vesicular Transport Proteins metabolism
Abstract

The mechanism of endoplasmic reticulum (ER)-Golgi complex (GC) traffic is conserved from yeast to higher animals, but the architectures and the dynamics of vesicles' traffic between ER and GC vary across cell types and species. Skeletal muscle is a unique tissue in which ER and GC undergo a structural reorganization during differentiation that completely remodels the secretory pathway. In mature skeletal muscle, the ER is turned into sarcoplasmic reticulum, which is composed of junctional and longitudinal regions specialized, respectively, in calcium release and uptake during contraction. During skeletal muscle differentiation, GC acquires a particular fragmented organization as it appears as spots both at the nuclear poles and along the fibers. The ubiquitary-expressed Yip1A isoform has been proposed to be involved in anterograde trafficking from the ER exit sites to the cis-side of the GC and in ER and GC architecture organization. We investigated the role of Yip1 in skeletal muscle. Here we report that, following skeletal muscle development, the expression of the Yip1A decreases and is replaced by the muscle-specific Yip1B isoform. Confocal microscope analysis revealed that in adult skeletal muscle the Yip1B isoform is localized in the ER-Golgi intermediate and cis-Golgi compartments. Finally, skeletal muscle knockdown experiments in vitro and in vivo suggested that Yip1B is not involved in GC structure maintenance.

Published
2015
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8. SCN5A allelic expression imbalance in African-Americans heterozygous for the common variant p.Ser1103Tyr.

Author

Killen SA, Kunic J, Wang L, Lewis A, Levy BP, Ackerman MJ, and George AL Jr

Subjects
Alleles, Allelic Imbalance, Death, Sudden, Genotype, Heterozygote, Humans, Infant, Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Sudden Infant Death epidemiology, Black or African American genetics, Sudden Infant Death genetics
Abstract

Background: Heterozygous and homozygous carriers of SCN5A-p.Ser1103Tyr, a common genetic variant with functional effects among African-Americans, have an increased risk of sudden death. We hypothesized that some heterozygous carriers may have unequal expression of wild-type and variant alleles and secondarily that predominance of the variant gene copy could further increase risk for sudden death in this population., Methods: We quantified allele-specific expression of SCN5A-p.Ser1103Tyr by real-time reverse-transcription polymerase chain reaction (RT-PCR) in heart tissue from heterozygous African-American infants, who died from sudden infant death syndrome (SIDS) or from other causes, to test for allelic expression imbalance., Results: We observed significant allelic expression imbalance in 13 of 26 (50%) African-American infant hearts heterozygous for SCN5A-p.Ser1103Tyr, and a significant (p < 0.0001) bimodal distribution of log2 allelic expression ratios. However, there were no significant differences in the mean log2 allelic expression ratios in hearts of infants dying from SIDS as compared to infants dying from other causes and no significant difference in the proportion of cases with greater expression of the variant allele., Conclusions: Our data provide evidence that SCN5A allelic expression imbalance occurs in African-Americans heterozygous for p.Ser1103Tyr, but this phenomenon alone does not appear to be a marker for risk of SIDS.

Published
2010
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