Similar Datasets
Project description:Loss of the PR domain 16 (PRDM16) genetic locus has been suggested as the needed trigger for the development of left ventricular non-compaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM) in patients with 1p36 deletion syndrome. Furthermore, lack of Prdm16 in the murine heart has recently been shown to cause a spectrum of cardiomyopathy phenotypes. In spite of these advances, our understanding of the downstream transcriptional pathways regulated by PRDM16 that lead to these cardiac phenotypes is limited. OBJECTIVE: to unveil the downstream transcriptional pathways involved in the development of cardiomyopathy phenotypes associated with PRDM16 mutations/deletion in human and mice. METHODS AND RESULTS: We hypothesized that PRDM16 acts as an upstream regulator of key transcriptional pathways involved in cardiac maturation. Induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with a PRDM16 variant, cardiac tissue from mice expressing the human variant, mice with cardiac-specific deletion of Prdm16 and in vitro gain and loss of Prdm16 function were employed. Here we show that de novo pathogenic variants in PRDM16 are sufficient to cause LVNC in humans. In contrast, haploinsufficiency or complete deletion of Prdm16 in cardiomyocytes in mice led to pathological hypertrophy and dilated cardiomyopathy respectively. We demonstrated that PRDM16 regulates cardiac maturation through the maintenance of estrogen-related receptors (ERRs) expression. By contrast, PRDM16 acts as a supressor of transforming growth factor beta (TGFB) signaling. CONCLUSIONS: PRDM16 is a novel regulator of cardiac maturation acting upstream of ERRs and their regulators, and a suppressor of fibrotic signaling including TGFB.
2023-12-01 | GSE193877 | GEO
Project description:Loss of the PR domain 16 (PRDM16) genetic locus has been suggested as the needed trigger for the development of left ventricular non-compaction cardiomyopathy (LVNC) and dilated cardiomyopathy (DCM) in patients with 1p36 deletion syndrome. Furthermore, lack of Prdm16 in the murine heart has recently been shown to cause a spectrum of cardiomyopathy phenotypes. In spite of these advances, our understanding of the downstream transcriptional pathways regulated by PRDM16 that lead to these cardiac phenotypes is limited. OBJECTIVE: to unveil the downstream transcriptional pathways involved in the development of cardiomyopathy phenotypes associated with PRDM16 mutations/deletion in human and mice. METHODS AND RESULTS: We hypothesized that PRDM16 acts as an upstream regulator of key transcriptional pathways involved in cardiac maturation. Induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with a PRDM16 variant, cardiac tissue from mice expressing the human variant, mice with cardiac-specific deletion of Prdm16 and in vitro gain and loss of Prdm16 function were employed. Here we show that de novo pathogenic variants in PRDM16 are sufficient to cause LVNC in humans. In contrast, haploinsufficiency or complete deletion of Prdm16 in cardiomyocytes in mice led to pathological hypertrophy and dilated cardiomyopathy respectively. We demonstrated that PRDM16 regulates cardiac maturation through the maintenance of estrogen-related receptors (ERRs) expression. By contrast, PRDM16 acts as a supressor of transforming growth factor beta (TGFB) signaling. CONCLUSIONS: PRDM16 is a novel regulator of cardiac maturation acting upstream of ERRs and their regulators, and a suppressor of fibrotic signaling including TGFB.
2023-12-01 | GSE193873 | GEO
Project description:Pathogenic variants in PRDM16 impair cardiomyocytes maturation and cause cardiomyopathy phenotypes in humans
| PRJNA798273 | ENA
Project description:Pathogenic variants in PRDM16 impair cardiomyocytes maturation and cause cardiomyopathy phenotypes in humans and mice
| PRJNA798271 | ENA
Project description:Pathogenic variants in PRDM16 impair cardiomyocytes maturation and cause cardiomyopathy phenotypes in mice
| PRJNA798263 | ENA
Project description:Teebi hypertelorism syndrome (THS; OMIM 145420) is a rare craniofacial disorder characterized by hypertelorism, prominent forehead, short nose with broad or depressed nasal root. Some cases of THS have been attributed to SPECC1L variants. Homozygous variants in CDH11 truncating the transmembrane and intracellular domains have been implicated in Elsahy-Waters syndrome (EWS; OMIM 211380) with hypertelorism. We report THS due to CDH11 heterozygous missense variants on 19 subjects from 9 families. All affected residues in the extracellular region of Cadherin-11 (CHD11) are highly conserved across vertebrate species and classical cadherins. Six of the variants that cluster around the EC2-EC3 and EC3-EC4 linker regions are predicted to affect Ca2+ binding that is required for cadherin stability. Two of the additional variants [c.164G > C, p.(Trp55Ser) and c.418G > A, p.(Glu140Lys)] are also notable as they are predicted to directly affect trans-homodimer formation. Immunohistochemical study demonstrates that CDH11 is strongly expressed in human facial mesenchyme. Using multiple functional assays, we show that five variants from the EC1, EC2-EC3 linker, and EC3 regions significantly reduced the cell-substrate trans adhesion activity and one variant from EC3-EC4 linker results in changes in cell morphology, focal adhesion, and migration, suggesting dominant negative effect. Characteristic features in this cohort included depressed nasal root, cardiac and umbilical defects. These features distinguished this phenotype from that seen in SPECC1L-related hypertelorism syndrome and CDH11-related EWS. Our results demonstrate heterozygous variants in CDH11, which decrease cell-cell adhesion and increase cell migratory behavior, cause a form of THS, as termed CDH11-related THS.
| S-EPMC9245547 | biostudies-literature
Project description:Oocyte maturation arrest is one of the important causes of female infertility, but the genetic factors remain largely unknown. PABPC1L, a predominant poly(A)-binding protein in Xenopus, mouse, and human oocytes and early embryos prior to zygotic genome activation, plays a key role in translational activation of maternal mRNAs. Here, we identified compound heterozygous and homozygous variants in PABPC1L that are responsible for female infertility mainly characterized by oocyte maturation arrest. In vitro studies demonstrated that these variants resulted in truncated proteins, reduced protein abundance, altered cytoplasmic localization, and reduced mRNA translational activation by affecting the binding of PABPC1L to mRNA. In vivo, three strains of Pabpc1l knock-in (KI) female mice were infertile. RNA sequencing analysis showed abnormal activation of the Mos-MAPK pathway in the zygotes of KI mice. Finally, we activated this pathway in mouse zygotes by injecting human MOS mRNA, and this mimicked the phenotype of KI mice. Our findings reveal the important roles of PABPC1L in human oocyte maturation and add a genetic potential candidate gene to be screened for causes of infertility.
| S-SCDT-10_15252-EMMM_202217177 | biostudies-other
Project description:Clinical, pathological, and genetic findings of a primary hereditary ataxia found in a Malinois dog family are described and compared with its human counterpart. Based on the family history and the phenotype/genotype relationships already described in humans and dogs, a causal variant was expected to be found in KCNJ10. Rather surprisingly, whole-exome sequencing identified the SLC12A6 NC_006612.3(XM_014109414.2): c.178_181delinsCATCTCACTCAT (p.(Met60Hisfs*14)) truncating variant. This loss-of-function variant perfectly segregated within the affected Malinois family in an autosomal recessive way and was not found in 562 additional reference dogs from 18 different breeds, including Malinois. In humans, SLC12A6 variants cause "agenesis of the corpus callosum with peripheral neuropathy" (ACCPN, alias Andermann syndrome), owing to a dysfunction of this K+-Cl- cotransporter. However, depending on the variant (including truncating variants), different clinical features are observed within ACCPN. The variant in dogs encodes the shortest isoform described so far and its resultant phenotype is quite different from humans, as no signs of peripheral neuropathy, agenesis of the corpus callosum nor obvious mental retardation have been observed in dogs. On the other hand, progressive spinocerebellar ataxia, which is the most important feature of the canine phenotype, hindlimb paresis, and myokymia-like muscle contractions have not been described in humans with ACCPN so far. As this is the first report of a naturally occurring disease-causing SLC12A6 variant in a non-human species, the canine model will be highly valuable to better understand the complex molecular pathophysiology of SLC12A6-related neurological disorders and to evaluate novel treatment strategies.
| S-EPMC6777613 | biostudies-literature
Project description:Nephrotic syndrome (NS) is a leading cause of chronic kidney disease. We found recessive NOS1AP variants in two families with early-onset NS by exome sequencing. Overexpression of wild-type (WT) NOS1AP, but not cDNA constructs bearing patient variants, increased active CDC42 and promoted filopodia and podosome formation. Pharmacologic inhibition of CDC42 or its effectors, formin proteins, reduced NOS1AP-induced filopodia formation. NOS1AP knockdown reduced podocyte migration rate (PMR), which was rescued by overexpression of WT Nos1ap but not by constructs bearing patient variants. PMR in NOS1AP knockdown podocytes was also rescued by constitutively active CDC42Q61L or the formin DIAPH3 Modeling a NOS1AP patient variant in knock-in human kidney organoids revealed malformed glomeruli with increased apoptosis. Nos1apEx3-/Ex3- mice recapitulated the human phenotype, exhibiting proteinuria, foot process effacement, and glomerulosclerosis. These findings demonstrate that recessive NOS1AP variants impair CDC42/DIAPH-dependent actin remodeling, cause aberrant organoid glomerulogenesis, and lead to a glomerulopathy in humans and mice.
| S-EPMC10763988 | biostudies-literature
Project description:Cardiac dysfunction is a common phenotypic manifestation of primary mitochondrial disease with multiple nuclear and mitochondrial DNA pathogenic variants as a cause, including disorders of mitochondrial translation. To date, five patients have been described with pathogenic variants in MRPL44, encoding the ml44 protein which is part of the large subunit of the mitochondrial ribosome (mitoribosome). Three presented as infants with hypertrophic cardiomyopathy, mild lactic acidosis, and easy fatigue and muscle weakness, whereas two presented in adolescence with myopathy and neurological symptoms. We describe two infants who presented with cardiomyopathy from the neonatal period, failure to thrive, hypoglycemia and in one infant lactic acidosis. A decompensation of the cardiac function in the first year resulted in demise. Exome sequencing identified compound heterozygous variants in the MRPL44 gene including the known pathogenic variant c.467 T > G and two novel pathogenic variants. We document a combined respiratory chain enzyme deficiency with emphasis on complex I and IV, affecting heart muscle tissue more than skeletal muscle or fibroblasts. We show this to be caused by reduced mitochondrial DNA encoded protein synthesis affecting all subunits, and resulting in dysfunction of complex I and IV assembly. The degree of oxidative phosphorylation dysfunction correlated with the impairment of mitochondrial protein synthesis due to different pathogenic variants. These functional studies allow for improved understanding of the pathogenesis of MRPL44-associated mitochondrial disorder.
| S-EPMC8289749 | biostudies-literature