A Novel Noonan Syndrome RAF1 Mutation: Lethal Course in a Preterm Infant

Ratola, Ana; Silva, Helena Moreira; Guedes, Ana; Mota, Céu; Braga, Adelaide; Oliveira, Dulce; Alegria, Artur; Carvalho, Cármen; Álvares, Sílvia; Proença, Elisa

doi:10.4081/pr.2015.5955

Cited by 10 publications

(9 citation statements)

References 8 publications

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“…However, recent genetic and molecular studies have demonstrated that most cardiomyopathy cases have genetic defects and some are inheritable [23]. So far, the common disease genes for HCM have been summarized as those of MYH7 , MYH6 , TPM1 and RAF1 [24–27]. In our study, we also identified that MYH7 mutation is one of the most common gene variants in HCM cases.…”

Section: Discussionsupporting

confidence: 66%

Green tea extract catechin improves cardiac function in pediatric cardiomyopathy patients with diastolic dysfunction

Quan

Jia

et al. 2019

J Biomed Sci

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Background Our previous studies have demonstrated that Ca 2+ desensitizing catechin could correct diastolic dysfunction in experimental animals with restrictive cardiomyopathy. In this study, it is aimed to assess the effects of green tea extract catechin on cardiac function and other clinical features in pediatric patients with cardiomyopathies. Methods Twelve pediatric cardiomyopathy patients with diastolic dysfunction were enrolled for the study. Echocardiography, ECG, and laboratory tests were performed before and after the catechin administration for 12 months. Comparison has been made in these patients before and after the treatment with catechin. Next Generation Sequencing was conducted to find out the potential causative gene variants in all patients. Results A significant decrease of isovolumetric relaxation time (115 ± 46 vs 100 ± 42 ms, P = 0.047 at 6 months; 115 ± 46 vs 94 ± 30 ms, P = 0.033 at 12 months), an increase of left ventricle end diastolic volume (40 ± 28 vs 53 ± 28 ml, P = 0.028 at 6 months; 40 ± 28 vs 48 ± 33 ml, P = 0.011 at 12 months) and stroke volume (25 ± 16 vs 32 ± 17 ml, P = 0.022 at 6 months; 25 ± 16 vs 30 ± 17 ml, P = 0.021 at 12 months) were observed with echocardiography in these patients 6-month after the treatment with catechin. Ejection fraction, left ventricular wall thickness, biatrial dimension remained unchanged. No significant side effects were observed in the patients tested. Conclusions This study indicates that Ca 2+ desensitizing green tea extract catechin, is helpful in correcting the impaired relaxation in pediatric cardiomyopathy patients with diastolic dysfunction. Electronic supplementary material The online version of this article (10.1186/s12929-019-0528-7) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 66%

Green tea extract catechin improves cardiac function in pediatric cardiomyopathy patients with diastolic dysfunction

Quan

Jia

et al. 2019

J Biomed Sci

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“…A total of 79.2% of pathogenic RAF1 alleles affect residues within the 14‐3‐3ζ recognition site of CR2, such as Arg256, Ser257, Ser259, Thr260, Pro261, Asn262, and Val263 (Kobayashi et al, ; Pandit et al, ; Razzaque et al, ; Sana et al, ); binding of RAF1 to 14‐3‐3ζ is critical for its autoinhibition (Kubicek et al, ; Light, Paterson, & Marais, ). The second group of mutations (8.1%) affects the adjacent residues Ser612 and Leu613 located C‐terminally to the CR3 domain, and the third group (7.9%) affects the two amino acid residues Asp486 and Thr491 within the activation segment of the kinase domain (Croonen et al, ; Hartill, Dillon, Warren, & Blyth, ; Hopper, Feinstein, Manning, Benitz, & Hudgins, ; Ko, Kim, Kim, & Yoo, ; Kobayashi et al, ; Pandit et al, ; Ratola et al, ; Razzaque et al, ; Sana et al, ; Schulz, Frober, Kraus, & Schneider, ). Only two amino acid substitutions in CR3 have been described so far (4%): p.(Ser427Gly) was found in mother and son with NS as well as in an unrelated patient (Kobayashi et al, ; Zebisch et al, ), and p.(Glu478Lys) was found in one patient (Ezquieta et al, ).…”

Section: Introductionmentioning

confidence: 99%

The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor

Harms

Alawi

Amor

et al. 2017

American J of Med Genetics Pt A

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Noonan syndrome is characterized by typical craniofacial dysmorphism, postnatal growth retardation, congenital heart defect, and learning difficulties and belongs to the RASopathies, a group of neurodevelopmental disorders caused by germline mutations in genes encoding components of the RAS-MAPK pathway. Mutations in the RAF1 gene are associated with Noonan syndrome, with a high prevalence of hypertrophic cardiomyopathy (HCM). RAF1 mutations cluster in exons encoding the conserved region 2 (CR2), the kinase activation segment of the CR3 domain, and the C-terminus. We present two boys with Noonan syndrome and the identical de novo RAF1 missense variant c.1082G>C/p.(Gly361Ala) affecting the CR3, but located outside the kinase activation segment. The p.(Gly361Ala) mutation has been identified as a RAF1 allele conferring resistance to RAF inhibitors. This amino acid change favors a RAF1 conformation that allows for enhanced RAF dimerization and increased intrinsic kinase activity. Both patients with Noonan syndrome showed typical craniofacial dysmorphism, macrocephaly, and short stature. One individual developed HCM and was diagnosed with a disseminated oligodendroglial-like leptomeningeal tumor (DOLT) of childhood at the age of 9 years. While there is a well-established association of NS with malignant tumors, especially childhood hemato-oncological diseases, brain tumors have rarely been reported in Noonan syndrome. Our data demonstrate that mutation scanning of the entire coding region of genes associated with Noonan syndrome is mandatory not to miss rare variants located outside the known mutational hotspots.

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“…In the literature, RAF1 is often implicated in Noonan syndrome cases diagnosed prenatally, in the first several weeks after birth, or on fetal autopsy. [57910] The trend in earlier diagnosis could point toward RAF1 mutations being either more severe or more clinically apparent than other forms of Noonan syndrome. Furthermore, mortality rate has been documented to be higher among this same set.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, mortality rate has been documented to be higher among this same set. [5710] Kobayashi et al have suggested that the remarkably higher incidence of heart conditions—including hypertrophic cardiomyopathy and biventricular hypertrophy—is likely responsible for this finding. [7]…”

Section: Discussionmentioning

confidence: 99%

Noonan syndrome associated with anomalous left coronary artery from the pulmonary artery in a patient with the rare RAF1 mutation: A case report and review of literature

et al. 2019

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We present the case of a 7-week-old male infant diagnosed with anomalous left coronary artery from the pulmonary artery (ALCAPA) who underwent repair by left coronary artery reimplantation, followed by an eventful postoperative period including need for venous arterial extracorporeal membrane oxygenation and mitral valve replacement due to mitral calcification and severe insufficiency. He also required heart transplant due to severe rapidly progressive biventricular hypertrophy. The pathology examination of the explanted heart showed massive cardiomegaly. Subsequently, the infant's cardiomyopathy panel was positive for RAF1 mutation, consistent with diagnosis of a rare form of Noonan syndrome. To our knowledge, this autosomal dominant condition in association with ALCAPA has not been previously reported in the literature.

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A Novel Noonan Syndrome RAF1 Mutation: Lethal Course in a Preterm Infant

Cited by 10 publications

References 8 publications

Green tea extract catechin improves cardiac function in pediatric cardiomyopathy patients with diastolic dysfunction

Green tea extract catechin improves cardiac function in pediatric cardiomyopathy patients with diastolic dysfunction

The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor

Noonan syndrome associated with anomalous left coronary artery from the pulmonary artery in a patient with the rare RAF1 mutation: A case report and review of literature

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