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FB2026_01
,
released March 12, 2026
This report describes Noonan syndrome with multiple lentigines 1 (NSML1, previously LEOPARD syndrome 1), which is a subtype of Noonan syndrome with multiple lentigines; NSML1 exhibits autosomal dominant inheritance. The human gene implicated in this disease is PTPN11, which encodes a protein-tyrosine phosphatase. This gene is also associated with Noonan syndrome 1 (MIM:163950; FBhh0000040), juvenile myelomonocytic leukemia (MIM:607785; FBhh0000578), and metachondromatosis (MIM:156250). There is one high-scoring fly ortholog, csw, for which RNAi targeting constructs, alleles caused by insertional mutagenesis, and classical amorphic alleles have been generated.
A transgenic construct of the wild-type human Hsap\PTPN11 gene under the control of a heat-shock promoter has been introduced into flies. Partial heterologous rescue (functional complementation) has been demonstrated: rescue of some, but not all, phenotypes of Dmel\csw null mutants is observed.
UAS constructs of the human Hsap\PTPN11 carrying variants implicated in disease have been introduced into flies. Variant(s) implicated in human disease tested (as transgenic human gene, PTPN11): the Y279C, R498W, Q510P, and Q510E variant forms of the human gene have been introduced into flies; the R498W variant form is also implicated in Noonan syndrome 1 (FBhh0000040). Experiments with the human variants include assessments of pharmaceutical candidates.
UAS constructs of Dmel\csw bearing mutations corresponding to NSML1 mutations in PTPN11 have been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): T588M in the fly csw gene (corresponds to T468M in the human PTPN11 gene); Y258C in the fly csw gene (corresponds to Y279C in the human PTPN11 gene). Both variants produce dominant gain-of-function phenotypes, which recapitulates observations in human.
Animals homozygous for amorphic mutations of Dmel\csw die during larval and pupal stages. Germline clones in females result in maternal-effect lethality during the embryonic stage; the embryos exhibit severe anatomical defects. Physical and genetic interactions of Dmel\csw have been described; see below and in the csw gene report.
[updated May 2021 by FlyBase; FBrf0222196]
The phenotypes typically observed include multiple lentigines (small pigmented skin spots), electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness (Gorlin et al., 1969; pubmed:5771505). [from MIM:151100; 2020.08.11]
[LEOPARD SYNDROME 1; LPRD1](https://omim.org/entry/151100)
[PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 11; PTPN11](https://omim.org/entry/176876)
LEOPARD syndrome (LPRD1) is an autosomal dominant disorder characterized by lentigines and cafe-au-lait spots, facial anomalies, and cardiac defects, sharing several clinical features with Noonan syndrome. [from MIM:176876, 2015.04.14]
This form of autosomal dominant LEOPARD syndrome, LPRD1, is caused by heterozygous mutation in the PTPN11 gene. [from MIM:151100, 2015.04.10]
Carvajal-Vergara et al., 2010, (pubmed:20535210) generated induced pluripotent stem cells (iPSCs) derived from 2 unrelated LEOPARD patients who were heterozygous for the T468M mutation in PTPN11. The iPSCs were extensively characterized and produced multiple differentiated cell lineages. A major disease phenotype in patients with LEOPARD syndrome is hypertrophic cardiomyopathy. This study showed that in vitro-derived cardiomyocytes from LEOPARD syndrome iPSCs are larger, have a higher degree of sarcomeric organization, and have preferential localization of the transcription factor NFATC4 in the nucleus when compared with cardiomyocytes derived from human embryonic stem cells or wildtype iPSCs derived from a healthy brother of one of the LEOPARD syndrome patients. These features correlate with a potential hypertrophic state. This study also provided molecular insights into signaling pathways that may promote the disease phenotype, and showed that basic fibroblast growth factor treatment increased the phosphorylation of ERK1/2 levels over time in several cell lines but did not have a similar effect in the LEOPARD syndrome iPSCs despite higher basal phosphorylated ERK levels in the LEOPARD syndrome iPSCs compared with the other cell lines. [from MIM:151100, 2015.04.10]
A study screened 9 patients with LEOPARD syndrome, and 2 children with Noonan syndrome who had multiple cafe-au-lait spots, for mutations in the PTPN11 gene. They found, in 10 of the 11 patients, 1 of 2 novel missense mutations, in exon 7 or exon 12. Both mutations affected the PTPN11 phosphotyrosine phosphatase domain, which is involved in less than 30% of the Noonan syndrome PTPN11 mutations. This study demonstrated that LEOPARD syndrome and Noonan syndrome are allelic disorders. The detected mutations suggested that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the LEOPARD syndrome subtype of Noonan syndrome (Digilio et al., 2002, pubmed:12058348). Kontaridis et al., 2006 (pubmed:16377799) examined the enzymatic properties of mutations in PTPN11 causing LEOPARD syndrome and found that, in contrast to the activating mutations that cause Noonan syndrome and neoplasia, LEOPARD syndrome mutants are catalytically defective and act as dominant-negative mutations that interfere with growth factor/ERK-MAPK -mediated signaling. Molecular modeling and biochemical studies suggested that LEOPARD syndrome mutations control the SHP2 catalytic domain and result in open, inactive forms of SHP2. This study concluded that the pathogenesis of LEOPARD syndrome is distinct from that of Noonan syndrome and suggested that these disorders should be distinguished by mutation analysis rather than clinical presentation. [from MIM:176876, 2015.04.14]
Many to one: 2 human to 1 Drosophila (See DIOPT, link below).
Ortholog of human PTPN11 and human PTPN6 (1 Drosophila to 2 human). Dmel\csw shares 40% identity and 52% similarity with human PTPN11, and 36% identity and 49% similarity with human PTPN6.