A novel PTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome

Sárközy, Anna; Obregón, María Gabriela; Conti, Emanuela; Esposito, Giulia; Mingarelli, Rita; Pizzuti, Antonio; Dallapiccola, Bruno

doi:10.1038/sj.ejhg.5201290

Cited by 47 publications

(28 citation statements)

References 16 publications

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“…We therefore speculate that additional factors (eg, modifier genes, epigenetic factors, or somatic 'second hits') contribute to the manifestation of MGCL in patients with NS, LS, CFCS, or NF1. The observations of a 'progressing phenotype' in individual patients 21 and of multiple family members affected by an NS-like disorder but being discordant for the presence of MGCL 19 support this hypothesis.…”

Section: -29supporting

confidence: 70%

Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome

et al. 2008

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Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS) are related developmental disorders caused by mutations in genes encoding various components of the RAS-MAPK signaling cascade. NS is associated with mutations in the genes PTPN11, SOS1, RAF1, or KRAS, whereas CFCS can be caused by mutations in BRAF, MEK1, MEK2, or KRAS. The NS phenotype is rarely accompanied by multiple giant cell lesions (MGCL) of the jaw (Noonan-like/MGCL syndrome (NL/MGCLS)). PTPN11 mutations are the only genetic abnormalities reported so far in some patients with NL/MGCLS and in one individual with LEOPARD syndrome and MGCL. In a cohort of 75 NS patients previously tested negative for mutations in PTPN11 and KRAS, we detected SOS1 mutations in 11 individuals, four of whom had MGCL. To explore further the relevance of aberrant RAS-MAPK signaling in syndromic MGCL, we analyzed the established genes causing CFCS in three subjects with MGCL associated with a phenotype fitting CFCS. Mutations in BRAF or MEK1 were identified in these patients. All mutations detected in these seven patients with syndromic MGCL had previously been described in NS or CFCS without apparent MGCL. This study demonstrates that MGCL may occur in NS and CFCS with various underlying genetic alterations and no obvious genotype -phenotype correlation. This suggests that dysregulation of the RAS-MAPK pathway

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Section: -29supporting

confidence: 70%

Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome

et al. 2008

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“…The spectrum of the so far described mutations in the PTPN11 gene in NS and LEOPARD syndrome as well as the available clinical phenotype of reported cases are presented in table 1 [7,8,9,10,11,12, 15, 17,19,20,21,22,23,24,25,26,27]. Apart from two trinucleotide deletions [10, 28], causative mutations are missense changes.…”

Section: Discussionmentioning

confidence: 99%

Does the Rare A172G Mutation of PTPN11 Gene Convey a Mild Noonan Syndrome Phenotype?

Kitsiou-Tzeli¹,

Papadopoulou

Kanaka‐Gantenbein

et al. 2006

Horm Res Paediatr

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Background: Noonan syndrome (NS) (OMIM 163950) is an autosomal dominant developmental disorder characterized mainly by typical facial dysmorphism, growth retardation and variable congenital heart defects. In unrelated individuals with sporadic or familial NS, heterozygous missense point mutations in the gene PTPN11 (OMIM 176876) have been confirmed, with a clustering of mutations in exons 3 and 8, the mutation A922G (Asn308Asp) accounting for nearly 25% of cases. Patient and Methods: We report a 7-year-old boy with short stature and some other clinical features of NS, who has been investigated by molecular analysis for the presence of mutations in the PTPN11 gene. Result: The de novo mutation A172G in the exon 3 of the PTPN11 gene, predicting an Asn58Asp substitution, has been found. To the best of our knowledge, this specific mutation has only been described once before, but this is the first report of detailed clinical data suggesting a mild phenotype. Conclusion: Detailed clinical phenotype in every patient with major or minor features of NS and molecular identification of PTPN11 gene mutation may contribute to a better phenotype–genotype correlation.

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“…Specifically, mutations of the tyrosine phosphatase SHP2 (an important regulator for receptor tyrosine kinase-mediated MAP kinase activation), [27][28][29][30] K-Ras, [31][32][33] and SOS1 (an essential Ras guanine-nucleotide exchange factor) 34 were found to cause Noonan syndrome, the most common single-gene cause of congenital heart diseases. 35,36 In addition, mutations in H-Ras, B-Raf, and MEK1/2 also were found to be responsible for the less frequent but related Costello syndrome and cardio-facio-cutaneous syndrome 33,37,38 in humans.…”

Section: Ras-erk Pathway In Cardiac Developmentmentioning

confidence: 99%

“…Ras-Raf-MEK-ERK Nanoon and Nanoon-like syndromes [27][28][29][30][31][32][33][34][35][36][37][38] Concentric hypertrophy1 54,55 ( [134][135][136] Eccentric hypertrophy12 [137][138][139]141 Cardiac protection1 142 Contractile dysfunction2 142 …”

Section: Developmental and Pathophysiological Roles Of Map Kinases Inmentioning

confidence: 99%

Mitogen-Activated Protein Kinases in Heart Development and Diseases

2007

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Abstract-Mitogen-activated protein (MAP) kinases belong to a highly conserved family of Ser-Thr protein kinases in the human kinome and have diverse roles in broad physiological functions. The 4 best-characterized MAP kinase pathways, ERK1/2, JNK, p38, and ERK5, have been implicated in different aspects of cardiac regulation, from development to pathological remodeling. Recent advancements in the development of kinase-specific inhibitors and genetically engineered animal models have revealed significant new insights about MAP kinase pathways in the heart. However, this explosive body of new information also has yielded many controversies about the functional role of specific MAP kinases as either detrimental promoters or critical protectors of the heart during cardiac pathological processes. These uncertainties have raised questions on whether/how MAP kinases can be targeted to develop effective therapies against heart diseases. In this review, recent studies examining the role of MAP kinase subfamilies in cardiac development, hypertrophy, and survival are summarized.

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A novel PTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome

Cited by 47 publications

References 16 publications

Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome

Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome

Does the Rare A172G Mutation of PTPN11 Gene Convey a Mild Noonan Syndrome Phenotype?

Mitogen-Activated Protein Kinases in Heart Development and Diseases

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