Genetic Modifiers for the Long-QT Syndrome

Background— Long-QT syndrome is an inherited cardiac channelopathy characterized by delayed repolarization, risk of life-threatening arrhythmia, and significant clinical variability even within families. Three single-nucleotide polymorphisms (SNPs) in the 3′ untranslated region of KCNQ1 were recently suggested to be associated with suppressed gene expression and hence decreased disease severity when located on the same haplotype with a disease-causing KCNQ1 mutation. We sought to replicate this finding in a larger and a genetically more homogeneous population of KCNQ1 mutation carriers. Methods and Results— The 3 SNPs (rs2519184, rs8234, and rs10798) were genotyped in a total of 747 KCNQ1 mutation carriers with A341V, G589D, or IVS7-2A>G mutation. The SNP haplotypes were assigned based on family trees. The SNP allele frequencies and clinical severity differed between the 3 mutation groups. The different SNP haplotypes were neither associated with heart rate–corrected QT interval duration (QTc) nor cardiac events in any of the 3 mutation groups. When the mutation groups were combined, the derived SNP haplotype of rs8234 and rs10798 located on the same haplotype with the mutation was associated with a shorter QTc interval ( P <0.05) and a reduced occurrence of cardiac events ( P <0.01), consistent with the previous finding. However, when the population-specific mutation was controlled for, both associations were no longer evident. Conclusions— 3′ Untranslated region SNPs are not acting as genetic modifiers in a large group of LQT1 patients. The confounding effect of merging a genetically and clinically heterogeneous group of patients needs to be taken into account when studying disease modifiers

Interplay of cell-cell contacts and RhoA/MRTF-A signaling regulates cardiomyocyte identity.

Cell-cell and cell-matrix interactions guide organ development and homeostasis by controlling lineage specification and maintenance, but the underlying molecular principles are largely unknown. Here, we show that in human developing cardiomyocytes cell-cell contacts at the intercalated disk connect to remodeling of the actin cytoskeleton by regulating the RhoA-ROCK signaling to maintain an active MRTF/SRF transcriptional program essential for cardiomyocyte identity. Genetic perturbation of this mechanosensory pathway activates an ectopic fat gene program during cardiomyocyte differentiation, which ultimately primes the cells to switch to the brown/beige adipocyte lineage in response to adipogenesis-inducing signals. We also demonstrate by in vivo fate mapping and clonal analysis of cardiac progenitors that cardiac fat and a subset of cardiac muscle arise from a common precursor expressing Isl1 and Wt1 during heart development, suggesting related mechanisms of determination between the two lineages

Congenital heart disease risk loci identified by genome-wide association study in European patients

Genetic factors undoubtedly affect the development of congenital heart disease (CHD) but still remain ill defined. We sought to identify genetic risk factors associated with CHD and to accomplish a functional analysis of SNP-carrying genes. We performed a genome-wide association study (GWAS) of 4034 White patients with CHD and 8486 healthy controls. One SNP on chromosome 5q22.2 reached genome-wide significance across all CHD phenotypes and was also indicative for septal defects. One region on chromosome 20p12.1 pointing to the MACROD2 locus identified 4 highly significant SNPs in patients with transposition of the great arteries (TGA). Three highly significant risk variants on chromosome 17q21.32 within the GOSR2 locus were detected in patients with anomalies of thoracic arteries and veins (ATAV). Genetic variants associated with ATAV are suggested to influence the expression of WNT3, and the variant rs870142 related to septal defects is proposed to influence the expression of MSX7. We analyzed the expression of all 4 genes during cardiac differentiation of human and murine induced pluripotent stem cells in vitro and by single-cell RNA-Seq analyses of developing murine and human hearts. Our data show that MACROD2, GOSR2, WNT3, and MSX7 play an essential functional role in heart development at the embryonic and newborn stages

Novel calmodulin mutations associated with congenital arrhythmia susceptibility.

BACKGROUND: Genetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden cardiac death in young adults and children. Recently, mutations in calmodulin (CALM1, CALM2) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype-phenotype correlations associated with calmodulin mutations. METHODS AND RESULTS: We used conventional and next-generation sequencing approaches, including exome analysis, in genotype-negative LQTS probands. We identified 5 novel de novo missense mutations in CALM2 in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. The clinical severity among subjects in this series was generally less than that originally reported for CALM1 and CALM2 associated with recurrent cardiac arrest during infancy. Four of 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca(2+)-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca(2+)-binding affinity. CONCLUSIONS: CALM2 mutations can be associated with LQTS and with overlapping features of LQTS and CPVT

Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: Is riboflavin supplementation effective?

Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and

Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?

BACKGROUND: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. RESULTS: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers. CONCLUSIONS: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin

Construyendo un nosotros. Arte interdisciplina y salud mental

Este proyecto de extensión acreditado y financiado por la UNLP, “Taller arte, recreando un nosotros” se propone promover prácticas alternativas de encuentro y participación colectiva para generar vínculos y relaciones no restrictivas entre internados, externados, familias, profesionales y no profesionales, en el Teatro del Hospital Alejandro Korn, utilizando el arte, la expresión, el juego y la estimulación de sentidos. Se sostiene en el proceso de reforma en materia de Salud Mental que se inicia con la Sanción de la Ley Nacional de Salud Mental (Ley Nº 26657) donde se busca continuar con el proceso de desmanicomialización que se viene llevando a cabo en todo el mundo y que registra antecedentes en las normativas internacionales (OPS, 1990; OPS, 2005; OPS, 2010). Se basa en el desplazamiento del eje de la atención brindada en el hospital psiquiátrico hacia estrategias de atención primaria de la salud con base en la comunidad. En los talleres se promueve la acción social concreta. La construcción de saberes se da conjuntamente con todos los involucrados. Actualmente funcionan talleres de radio, arte y expresión, expresión literaria y jardín de sensaciones. Siendo espacios de producción, de aprendizaje, de circulación de la palabra, de compartir con el otro experiencias de vida y opiniones en donde se rescata la subjetividad, la identidad e historicidad. Fuera del hospital se realizan reuniones de planificación y/ contención, trabajando lo emocional y la grupalidad de los talleristas intervinientes. Estos espacios parten del encuentro INTERDISCIPLINAR, quienes participan son de distintas disciplinas tales como psicología, bellas artes, comunicación social, trabajo social, acompañantes terapéuticos, antropología; articulando el trabajo con otros grupos pertenecientes al hospital, instituciones universitarias y otras organizaciones. El trabajo colectivo interdisciplinar se vuelve uno de los pilares así como el ARTE en tanto medio de expresión y no como fin estético. Lo artístico como lenguaje de comunicación, socialización y como herramienta de expansión de la subjetividad en un espacio determinado, un lugar de salud. Desde la continuidad de las actividades y encuentros se producen cambios subjetivos en los participantes. En ese sentido la apuesta es producir una transformación en lo cotidiano de cada uno para que eso sea retomado en los diferentes dispositivos y actores que apuestan a una externación o mejor condición de la persona internada y una mejoría en la salud mental y salud en general. Palabras claves: práctica transformadora, subjetividad, arte, interdisciplina, salud mental

Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies

Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure. Although C1QBP has been reported to exert pleiotropic effects on many cellular processes, we report here four individuals from unrelated families where biallelic mutations in C1QBP cause a defect in mitochondrial energy metabolism. Infants presented with cardiomyopathy accompanied by multisystemic involvement (liver, kidney, and brain), and children and adults presented with myopathy and progressive external ophthalmoplegia. Multiple mitochondrial respiratory-chain defects, associated with the accumulation of multiple deletions of mitochondrial DNA in the later-onset myopathic cases, were identified in all affected individuals. Steady-state C1QBP levels were decreased in all individuals’ samples, leading to combined respiratory-chain enzyme deficiency of complexes I, III, and IV. C1qbp−/− mouse embryonic fibroblasts (MEFs) resembled the human disease phenotype by showing multiple defects in oxidative phosphorylation (OXPHOS). Complementation with wild-type, but not mutagenized, C1qbp restored OXPHOS protein levels and mitochondrial enzyme activities in C1qbp−/− MEFs. C1QBP deficiency represents an important mitochondrial disorder associated with a clinical spectrum ranging from infantile lactic acidosis to childhood (cardio)myopathy and late-onset progressive external ophthalmoplegia

Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies

Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure. Although C1QBP has been reported to exert pleiotropic effects on many cellular processes, we report here four individuals from unrelated families where biallelic mutations in C1QBP cause a defect in mitochondrial energy metabolism. Infants presented with cardiomyopathy accompanied by multisystemic involvement (liver, kidney, and brain), and children and adults presented with myopathy and progressive external ophthalmoplegia. Multiple mitochondrial respiratory-chain defects, associated with the accumulation of multiple deletions of mitochondrial DNA in the later-onset myopathic cases, were identified in all affected individuals. Steady-state C1QBP levels were decreased in all individuals' samples, leading to combined respiratory-chain enzyme deficiency of complexes I, III, and IV. C1qbp(-/-) mouse embryonic fibroblasts (MEFs) resembled the human disease phenotype by showing multiple defects in oxidative phosphorylation (OXPHOS). Complementation with wild-type, but not mutagenized, C1qbp restored OXPHOS protein levels and mitochondrial enzyme activities in C1qbp(-/-) MEFs. C1QBP deficiency represents an important mitochondrial disorder associated with a clinical spectrum ranging from infantile lactic acidosis to childhood (cardio)myopathy and late-onset progressive external ophthalmoplegia.This study was supported by the German BMBF and Horizon2020 through E-Rare project GENOMIT (01GM1603 and 01GM1207 to H.P.; FWF-I 2741-B26 to J.A.M.); Vereinigung zur Förderung Pädiatrischer Forschung Salzburg; EU FP7 MEET Project (317433 to H.P. and J.A.M.); Horizon2020 Project SOUND (633974 to H.P.); Marie Skłodowska-Curie Actions Reintegration Fellowship (Mitobiopath-705560 to C.G.); UK NHS Highly Specialised Mitochondrial Service (R.W.T.); Wellcome Centre for Mitochondrial Research (203105/Z/16 to Z.M.C.-L., R.N.L., and R.W.T.); MRC Centre for Neuromuscular Diseases (G0601943 to R.W.T. and P.F.C.); Lily Foundation (R.W.T. and K.T.); UK NIHR fellowship (NIHR-HCS-D12-03-04 to C.L.A.); Wellcome Senior Fellowship (101876/Z/13/Z to P.F.C.); UK NIHR award and MRC Mitochondrial Biology Unit (MC_UP_1501/2 to P.F.C.); NIH (R01 GM0077465 and R35 GM122455 to V.K.M.); EMBO fellowship (ALTF 554-2015 to A.A.J.); UK MRC core funding for the Mitochondrial Biology Unit of the University of Cambridge (MC_U105697135 to A.R.D., P.R.G., and M. Minczuk); Portuguese Fundação para a Ciência e a Tecnologia (PD/BD/105750/2014 to P.R.G.); Italian Telethon (GSP16001 to G.P.C.); Fondazione Cariplo (2014-1010 to D.R.); Strategic Research Center in Private Universities from MEXT; and Practical Research Project for Rare/Intractable Diseases from AMED