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Q241R mutation of Braf gene causes neurological abnormalities in a mouse model of cardio-facio-cutaneous syndrome independent of developmental malformations

ABSTRACT: Q241R mutation of Braf gene causes neurological abnormalities in a mouse model of cardio-facio-cutaneous syndrome independent of developmental malformations

PROVIDER: PRJNA984224 | ENA |

REPOSITORIES: ENA

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Q241R mutation of Braf gene causes neurological abnormalities in a mouse model of cardio-facio-cutaneous syndrome independent of developmental malformations

Project description:Constitutively active mutants of Braf cause cardio-facio-cutaneous (CFC) syndrome, which is characterized by growth and developmental defects, cardiac malformations, characteristic facial features, cutaneous manifestations, and mental retardation. An animal model of human CFC syndrome, a systemic BrafQ241R/+ mutant mouse has been reported to exhibit multiple CFC syndrome-like phenotypes. In this study, we analyzed the effects of Braf mutation on neural functions separately from their effects on developmental processes. To this end, we generated Braf mutant mice that express BrafQ241R specifically in mature excitatory neurons (n-BrafQ241R/+). We found no growth retardation or cardiac malformations in n-BrafQ241R/+ mice, indicating normal development of these mice. Behavioral analysis revealed that the mutant mice exhibited decreased locomotor activity and exploratory behavior, enhanced auditory startle response, and impaired hippocampus-dependent learning, many of which were similar to the systemic BrafQ241R/+ mouse. In the hippocampus of n-BrafQ241R/+ mice, the long-term potentiation of synaptic transmission was enhanced, and active forms of ERK1/2 were increased. Transcriptome analysis of hippocampal tissue revealed significant changes in the expression of genes involved in synaptic function and memory learning, as well as increased expression of Dusp6 and Spred3, suppressors of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway. These data suggest that the neuronal dysfunction observed in the systemic CFC mouse model is due to the disruption of homeostasis of RAS/MAPK signaling pathway by the activated Braf mutant after maturation, rather than abnormal development of the brain, and a similar mechanism may be possible in human CFC syndrome.

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BCOR-regulated genes in human oculo-facio-cardio-dental syndrome

Project description:Oculo-facio-cardio-dental syndrome (OFCD) is a rare genetic disorder characterized by teeth with extremely long roots (radiculomegaly), and craniofacial, eye and cardiac abnormalities. The mutation of the transcriptional co-repressor BCOR has been identified as being responsible for oculo-facio-cardio-dental (OFCD) syndrome. Mesenchymal stem cells (MSCs) is isolated from the root apical papilla of an OFCD patient. Gene expression profiling is performed and compared between mutant MSCs and wild type MSCs. Total RNA were extracted from normal MSCs (MSCWT) and mutant MSCs (MSCO).

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BCOR-regulated genes in human oculo-facio-cardio-dental syndrome

2009-07-23 | GSE15214 | GEO

SMCHD1 variants induce variegated expression in Facio Scapulo Humeral Dystrophy and Bosma Arhinia and microphtalmia syndrome (Methylation).

Project description:Determination of SMCHD1 epi-signature in type 2 Facio Scapulo Humeral Dystrophy (FSHD2) and Bosma Arhinia and Microphtalmia Syndrome (BAMS).

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SMCHD1 variants induce variegated expression in Facio Scapulo Humeral Dystophy and Bosma Arhinia and microphtalmia syndrome (ChIP-Seq).

Project description:Determination of SMCHD1 epi-signature in type 2 Facio Scapulo Humeral Dystrophy (FSHD2) and Bosma Arhinia and Microphtalmia Syndrome (BAMS).

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SMCHD1 variants induce variegated expression in Facio Scapulo Humeral Dystophy and Bosma Arhinia and microphtalmia syndrome. [ChIP-Seq]

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SMCHD1 variants induce variegated expression in Facio Scapulo Humeral Dystophy and Bosma Arhinia and microphtalmia syndrome. [RNA-Seq]

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Oculo-facio-cardio-dental (OFCD) syndrome: a case report.

Project description:BackgroundOculo-facio-cardio-dental (OFCD) syndrome is a rare condition that affects the eyes, face, heart, and teeth of patients. One notable dental characteristic of OFCD is radiculomegaly, or root gigantism, which highlights the role of dentists in detecting this syndrome. OFCD is an X-linked dominant syndrome that results from a variant in the BCOR gene. Our study presents the first documented case of OFCD in Vietnam and reports a novel BCOR gene variant observed in this case.Case presentationA 19-year-old Vietnamese female patient with an extremely long root with an abscess was clinically examined for the expression of OFCDs. The radiograph and the variant in BCOR gene were also evaluated. We identified abnormalities in the teeth, as well as ocular, facial, and cardiac features, with radiculomegaly of the canines being a specific symptom for OFCDs. The patient's genetic analysis revealed a pathogenic heterozygous deletion at intron 11 of the BCOR gene, representing a novel variant.ConclusionOculo-facio-cardio-dental syndrome (OFCD) is an extremely rare condition characterized by abnormalities in the eyes, face, heart, and teeth, often caused by variants in the BCOR gene. Radiculomegaly, or enlarged dental roots, is a key diagnostic feature of OFCD, and early detection is crucial for preventing future dental complications.

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Up-regulation of prolactin receptor in the proximal tubular cells in cardio-renal syndrome model mice

Project description:The precise physiological mechanisms of cardio-renal syndrome are yet to be elucidated. In order to investigate the molecular basis of cardio-renal syndrome, we established a mouse model for cardio-renal syndrome by the combination of abdominal aortic banding and uninephrectomy. Renal function of the cardio-renal syndrome mice was synergistically decreased compared with that of mice that underwent uninephrectomy alone. To investigate the molecules involved in the deterioration renal function in the AbNx mice, we conducted comprehensive gene expression analysis using DNA array by comparing the molecules expressed in the remained kidney of AbNx mice with those of Nx mice.

2012-03-19 | GSE36591 | GEO

Mek1Y130C mice recapitulate aspects of human cardio-facio-cutaneous syndrome.

Project description:The RAS/MAPK signaling pathway is one of the most investigated pathways, owing to its established role in numerous cellular processes and implication in cancer. Germline mutations in genes encoding members of the RAS/MAPK pathway also cause severe developmental syndromes collectively known as RASopathies. These syndromes share overlapping characteristics, including craniofacial dysmorphology, cardiac malformations, cutaneous abnormalities and developmental delay. Cardio-facio-cutaneous syndrome (CFC) is a rare RASopathy associated with mutations in BRAF, KRAS, MEK1 (MAP2K1) and MEK2 (MAP2K2). MEK1 and MEK2 mutations are found in ?25% of the CFC patients and the MEK1Y130C substitution is the most common one. However, little is known about the origins and mechanisms responsible for the development of CFC. To our knowledge, no mouse model carrying RASopathy-linked Mek1 or Mek2 gene mutations has been reported. To investigate the molecular and developmental consequences of the Mek1Y130C mutation, we generated a mouse line carrying this mutation. Analysis of mice from a Mek1 allelic series revealed that the Mek1Y130C allele expresses both wild-type and Y130C mutant forms of MEK1. However, despite reduced levels of MEK1 protein and the lower abundance of MEK1 Y130C protein than wild type, Mek1Y130C mutants showed increased ERK (MAPK) protein activation in response to growth factors, supporting a role for MEK1 Y130C in hyperactivation of the RAS/MAPK pathway, leading to CFC. Mek1Y130C mutant mice exhibited pulmonary artery stenosis, cranial dysmorphia and neurological anomalies, including increased numbers of GFAP+ astrocytes and Olig2+ oligodendrocytes in regions of the cerebral cortex. These data indicate that the Mek1Y130C mutation recapitulates major aspects of CFC, providing a new animal model to investigate the physiopathology of this RASopathy. This article has an associated First Person interview with the first author of the paper.

| S-EPMC5897723 | biostudies-literature

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