Noonan Syndrome with Multiple Lentigines (NSML; formerly called Leopard syndrome [LS]) is an autosomal dominant "RASopathy" characterized by multiple brown skin spots (lentigines), congenital heart disease, short stature, genital abnormalities, hearing loss and distinctive facial features. In humans, the PTPN11*Y279C mutation is one of the two most common NSML mutations.
The ubiquitously expressing (non-inducible) NSML knock-in allele (Ptpn11Y279C) encodes the Ptpn11*Y279C mutant protein. Mice heterozygous for this allele (Ptpn11Y279C/+ or NSML/+; formerly LS/+) recapitulate several characteristics of the human disorder. Morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy is evident by 12 weeks of age.
NSML/+ mice may also exhibit any of the following at variable penetrance: craniofacial dysmorphia, skeletal/chest abnormalities, shorter stature compared to wildtype mice. Heterozygous mice exhibit premature lethality (~25% die between 8-12 months of age), and surviving NSML/+ mice of both sexes are viable and fertile to at least 12 months of age.
In addition, heterozygotes have abnormal genitalia and substantial macrophage accumulation in the organ of Corti (inner ear). Importantly, treatment with the mTOR-inhibitor rapamycin effectively reverses the NSML disease phenotype.
Specifically, NSML/+ mice have hypertelorism appearance (abnormal faces, with distinctly smaller, more slanted eyes and a planar nasal bridge). Heart and/or cardiomyocyte lysates from NSML/+ mice show enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. NSML/+ mice also exhibited increased basal and agonist-induced Akt and mTor activity. The donating investigator reports they keep breeding units between 4-8 months of age, and abnormal genitalia can sometimes delay breeding by heterozygous males.
Expression of this Ptpn11Y279C knock-in allele (both mRNA and protein) is at levels comparable to wildtype Ptpn11. Peripheral blood, bone marrow, spleen, and thymus from NSML/+ mice show no apparent abnormalities in any hematological parameter.
The donating investigator reports that homozygous mice (Ptpn11Y279C/Y279C or NSML/NSML; formerly LS/LS) exhibit a more severe phenotype and ~50% of homozygotes mice die between 8-12 months of age. Homozygous mice are born at significantly reduced frequency, and homozygous females do not lactate.
