The leopard (multiple lentigines) syndrome revisited

Gorlin, Robert J.; Anderson, Ray C.; Moller, James H.

doi:10.1288/00005537-197110000-00015

Cited by 70 publications

(102 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Indeed, LS patients also are not reported to have any highly penetrant hematological abnormalities. Taken together, these data indicate that the gross morphologic features in LS/+ mice closely recapitulate those in LS patients (20,31,55).…”

Section: Generation Of Mice Expressing An Inducible Ptpn11 Y279c Allelesupporting

confidence: 64%

“…Essentially all cases of LEOPARD syndrome (LS) (MIM151100), a rare autosomal dominant, multisystemic disease, are caused by mutations in PTPN11 (19). LS is named for its presenting manifestations: multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness (20). PTPN11 mutations also cause more than 45% of cases of Noonan syndrome (NS) (MIM163950) (21), the more common disorder (~1/2,000 births), with the remaining cases resulting from mutations in SOS1 (22,23), KRAS (24), NRAS (25), SHOC2 (26), RAF1 (27,28), or as yet unknown genes.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Marin

Keith²,

Davies³

et al. 2011

J. Clin. Invest.

248

270

View full text Add to dashboard Cite

LEOPARD syndrome (LS) is an autosomal dominant "RASopathy" that manifests with congenital heart disease. Nearly all cases of LS are caused by catalytically inactivating mutations in the protein tyrosine phosphatase (PTP), non-receptor type 11 (PTPN11) gene that encodes the SH2 domain-containing PTP-2 (SHP2). RASopathies typically affect components of the RAS/MAPK pathway, yet it remains unclear how PTPN11 mutations alter cellular signaling to produce LS phenotypes. We therefore generated knockin mice harboring the Ptpn11 mutation Y279C, one of the most common LS alleles. Ptpn11 Y279C/+ (LS/+) mice recapitulated the human disorder, with short stature, craniofacial dysmorphia, and morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy (HCM). Heart and/or cardiomyocyte lysates from LS/+ mice showed enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. LS/+ mice also exhibited increased basal and agonist-induced Akt and mTor activity. The cardiac defects in LS/+ mice were completely reversed by treatment with rapamycin, an inhibitor of mTOR. Our results demonstrate that LS mutations have dominant-negative effects in vivo, identify enhanced mTOR activity as critical for causing LS-associated HCM, and suggest that TOR inhibitors be considered for treatment of HCM in LS patients.

show abstract

Section: Generation Of Mice Expressing An Inducible Ptpn11 Y279c Allelesupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

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

Marin

Keith²,

Davies³

et al. 2011

J. Clin. Invest.

248

270

View full text Add to dashboard Cite

show abstract

“…1 NS shares several features with multiple lentigines (ML)/LEOPARD syndrome (LS), a distinct condition with short stature, CHD, ML, electrocardiographic conduction abnormalities and sensorineural deafness. 2,3 NS and LS are allelic conditions, caused by different missense mutations in PTPN11 gene, on chromosome 12q24, even if genetic heterogeneity has been documented for both disorders. 4 -9 In 1974, Cohen et al described a patient with short stature, moderate developmental delay, facial dysmorphisms, short webbed neck, PVS, ML, pectus excavatum, cubitus valgus, generalised hypomineralisation, hearing loss, multiple central giant cell lesions (MGCL) of bones, joints and/or soft tissues, and considered this association as an entity sui generis.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2004

View full text Add to dashboard Cite

Noonan (NS) and multiple lentigines/LEOPARD syndromes (LS) have proved to be associated with distinct PTPN11 mutations. Noonan-like/multiple giant cell lesion syndrome (NLS) is a rare disease, characterised by short stature, facial dysmorphisms, congenital heart defect (CHD) and central giant cell lesions. PTPN11 gene mutations have been reported in a single NLS family and two sporadic patients. Here we report a patient with a complex phenotype progressing throughout the years from NS at birth towards LS and NLS. PTPN11 gene analysis disclosed a novel missense mutation (Ala461Thr) in exon 12, affecting the consensus sequence of the SHP2-active site. This observation joins together NS and LS to NLS into a unique genetic defect, broadening the clinical and molecular spectrum of PTPN11-related disorders.

show abstract

“…Electrocardiographic abnormalities, ocular telorism, pulmonary valve stenosis, abnormal genitalia, retardation of growth and deafness. 9 The lentigines are dark brown irregularly shaped macules ranging in size from pinpoint to 5 cm with involvement of the face, neck and upper trunk. The extremities and genitalia are less commonly involved.…”

Section: Leopard Syndromementioning

confidence: 99%