scholarly journals Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome–associated PTPN11 mutation

2011 ◽  
Vol 121 (3) ◽  
pp. 1026-1043 ◽  
Author(s):  
Talita M. Marin ◽  
Kimberly Keith ◽  
Benjamin Davies ◽  
David A. Conner ◽  
Prajna Guha ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Mouse Model ◽  
Leopard Syndrome ◽  
Ptpn11 Mutation

scholarly journals LEOPARD syndrome in an infant with severe hypertrophic cardiomyopathy and PTPN11 mutation

2011 ◽  
Vol 4 (1) ◽  
pp. 74 ◽  
Author(s):  
Madhusudan Ganigara ◽  
Atul Prabhu ◽  
RaghvannairSuresh Kumar
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Leopard Syndrome ◽  
Ptpn11 Mutation

Ventricular arrhythmias and remodeling in a mouse model of hypertrophic cardiomyopathy

2018 ◽  
Vol 120 ◽  
pp. 30-31
Author(s):  
F. Flenner ◽  
N. Küpker ◽  
F.W. Friedrich ◽  
C. Jungen ◽  
M. Kruse ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Mouse Model ◽  
Ventricular Arrhythmias

scholarly journals Efficient Correction of a Hypertrophic Cardiomyopathy Mutation by ABEmax-NG

2021 ◽  
Author(s):  
Shuhong Ma ◽  
Wenjian Jiang ◽  
Xujie Liu ◽  
Wen-Jing Lu ◽  
Tao Qi ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Mouse Model ◽  
Pathogenic Mutation ◽  
Adeno Associated Virus ◽  
Vitro Fertilization ◽  
Base Editing ◽  
Dna And Rna ◽  
Hereditary Disorders

Rationale: Genetic editing has shown great potential for the treatment of human hereditary disorders via the elimination of mutations in embryos. However, the efficiency and safety of germline gene editing are not well understood. Objective: We aimed to examine the preclinical efficacy/safety of embryonic base editing in a mouse model of hypertrophic cardiomyopathy (HCM) using a novel adenine base editor (ABE) platform. Methods and Results: Here, we described the use of an ABEmax-NG to directly correct the pathogenic R404Q/+ mutation (Myh6 c.1211C>T) in embryos for a mouse model of HCM, increasing the number of wild-type embryos for in vitro fertilization. Delivery of the ABEmax-NG mRNA to embryos from R404Q/+ HCM mice resulted in 62.5-70.8% correction of the Myh6 c.1211C>T, reducing the level of mutant RNA and eliminating HCM in the post-natal mice as well as their offspring. In addition, the same sgRNA was also used to target an intronic locus (TGG PAM) with an overall editing rate of 86.7%, thus confirming that ABEmax-NG can efficiently edit target loci with different PAMs (NG) and genomic distribution in vivo. Compared with CRISPR/ssODN-mediated correction, ABEmax-NG displayed a much higher correction rate without introducing indels. DNA and RNA off-target analysis did not detect off-target editing in treated embryos and founder mice. In utero injection of adeno-associated virus 9 (AAV9) encoding the ABEmax-NG also resulted in around 25.3% correction of the pathogenic mutation and reduced of mutant RNA, thereby indicating ABEmax-NG has the potential to correct the HCM mutation in vivo. Conclusions: We developed an ABEmax-NG system, which efficiently corrected a pathogenic Myh6 HCM mutation in mouse embryos without off target lesions, thus safely eliminating HCM in derived mice and their progeny.

scholarly journals Effects of nicotine administration in a mouse model of familial hypertrophic cardiomyopathy, α-tropomyosin D175N

2011 ◽  
Vol 301 (4) ◽  
pp. H1646-H1655 ◽  
Author(s):  
Robert D. Gaffin ◽  
Shamim A. K. Chowdhury ◽  
Marco S. L. Alves ◽  
Fernando A. L. Dias ◽  
Cibele T. D. Ribeiro ◽  
...  
Keyword(s):  
Heart Rate ◽  
Hypertrophic Cardiomyopathy ◽  
Mouse Model ◽  
Troponin I ◽  
Left Ventricular ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Maximal Rate ◽  
Western Blots ◽  
Nicotine Administration ◽  
Acute And Chronic Effects

The effects of nicotine (NIC) on normal hearts are fairly well established, yet its effects on hearts displaying familial hypertrophic cardiomyopathy have not been tested. We studied both the acute and chronic effects of NIC on a transgenic (TG) mouse model of FHC caused by a mutation in α-tropomyosin (Tm; i.e., α-Tm D175N TG, or Tm175). For acute effects, intravenously injected NIC increased heart rate, left ventricular (LV) pressure, and the maximal rate of LV pressure increase (+dP/d t) in non-TG (NTG) and Tm175 mice; however, Tm175 showed a significantly smaller increase in the maximal rate of LV pressure decrease (−dP/ dt) compared with NTGs. Western blots revealed phosphorylation of phospholamban Ser16 and Thr17 residue increased in NTG mice following NIC injection but not in Tm175 mice. In contrast, phosphorylation of troponin I at serine residues 23 and 24 increased equally in both NTG and Tm175. Thus the attenuated increase in relaxation in Tm175 mice following acute NIC appears to result primarily from attenuated phospholamban phosphorylation. Chronic NIC administration (equivalent to smoking 2 packs of cigarettes/day for 4 mo) also increased +dP/dt in NTG and Tm175 mice compared with chronic saline. However, chronic NIC had little effect on heart rate, LV pressure, −dP/d t, LV wall and chamber dimensions, or collagen content for either group of mice.

Blocking cardiac growth in hypertrophic cardiomyopathy induces cardiac dysfunction and decreased survival only in males

2007 ◽  
Vol 292 (2) ◽  
pp. H838-H845 ◽  
Author(s):  
Stephen W. Luckey ◽  
Jason Mansoori ◽  
Kelly Fair ◽  
Christopher L. Antos ◽  
Eric N. Olson ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Mouse Model ◽  
Glycogen Synthase ◽  
Contractile Function ◽  
Premature Death ◽  
Contractile Dysfunction ◽  
Sexually Dimorphic ◽  
Cardiac Growth ◽  
Hypertrophic Growth ◽  
Gsk 3Β

Mutations in myosin heavy chain (MyHC) can cause hypertrophic cardiomyopathy (HCM) that is characterized by hypertrophy, histopathology, contractile dysfunction, and sudden death. The signaling pathways involved in the pathology of HCM have not been elucidated, and an unresolved question is whether blocking hypertrophic growth in HCM may be maladaptive or beneficial. To address these questions, a mouse model of HCM was crossed with an antihypertrophic mouse model of constitutive activated glycogen synthase kinase-3β (caGSK-3β). Active GSK-3β blocked cardiac hypertrophy in both male and female HCM mice. However, doubly transgenic males (HCM/GSK-3β) demonstrated depressed contractile function, reduced sarcoplasmic (endo) reticulum Ca2+-ATPase (SERCA) expression, elevated atrial natriuretic factor (ANF) expression, and premature death. In contrast, female HCM/GSK-3β double transgenic mice exhibited similar cardiac histology, function, and survival to their female HCM littermates. Remarkably, dietary modification from a soy-based diet to a casein-based diet significantly improved survival in HCM/GSK-3β males. These findings indicate that activation of GSK-3β is sufficient to limit cardiac growth in this HCM model and the consequence of caGSK-3β was sexually dimorphic. Furthermore, these results show that blocking hypertrophy by active GSK-3β in this HCM model is not therapeutic.

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