ArticleAmerican journal of human genetics2013
Age-dependent germline mosaicism of the most common noonan syndrome mutation shows the signature of germline selection.
Article in American journal of human genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 62 citations in OpenAlex.
- Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders.Molecular syndromology · 2026Article
- Stem cell competition.Current topics in developmental biology · 2026Review
- Male gamete copies to characterize genome inheritance and generate progenies.Scientific reports · 2025Article
- Germline mosaicism in TCF20-associated neurodevelopmental disorders: a case study and literature review.Journal of human genetics · 2025Review
- Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Human embryonic genetic mosaicism and its effects on development and disease.Nature reviews. Genetics · 2024Review
- SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline.American journal of human genetics · 2024Article
- Exploring FGFR3 Mutations in the Male Germline: Implications for Clonal Germline Expansions and Paternal Age-Related Dysplasias.Genome biology and evolution · 2024Article
- Exploring the Micro-Mosaic Landscape ofGenes · 2024Article
- The impact of paternal age on new mutations and disease in the next generation.Fertility and sterility · 2022Review
- Article
- Discovery of an unusually high number of de novo mutations in sperm of older men using duplex sequencing.Genome research · 2022Article
- Pathogenic postzygotic mosaicism in the tyrosine receptor kinase pathway: potential unidentified human disease hidden away in a few cells.The FEBS journal · 2021Review
- A case of germline mosaicism for a 7q32.1q33 deletion in a sperm donor: consequences on pregnancy follow-up and recommendations.Basic and clinical andrology · 2020Article
- Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome.Clinical genetics · 2019Article
- Prenatal diagnosis for de novo mutations: Experience from a tertiary center over a 10-year period.Molecular genetics & genomic medicine · 2019Article
- Low-level parental mosaicism affects the recurrence risk of holoprosencephaly.Genetics in medicine : official journal of the American College of Medical Genetics · 2019Article
- Achondroplasia: a comprehensive clinical review.Orphanet journal of rare diseases · 2019Review
- RAS GTPase-dependent pathways in developmental diseases: old guys, new lads, and current challenges.Current opinion in cell biology · 2018Review
- Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes.Genome research · 2018Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Noonan syndrome (NS) is among the most common Mendelian genetic diseases (∼1/2,000 live births). Most cases (50%-84%) are sporadic, and new mutations are virtually always paternally derived. More than 47 different sites of NS de novo missense mutations are known in the PTPN11 gene that codes for the protein tyrosine phosphatase SHP-2. Surprisingly, many of these mutations are recurrent with nucleotide substitution rates substantially greater than the genome average; the most common mutation, c.922A>G, is at least 2,400 times greater. We examined the spatial distribution of the c.922A>G mutation in testes from 15 unaffected men and found that the mutations were not uniformly distributed across each testis as would be expected for a mutation hot spot but were highly clustered and showed an age-dependent germline mosaicism. Computational modeling that used different stem cell division schemes confirmed that the data were inconsistent with hypermutation, but consistent with germline selection: mutated spermatogonial stem cells gained an advantage that allowed them to increase in frequency. SHP-2 interacts with the transcriptional activator STAT3. Given STAT3's function in mouse spermatogonial stem cells, we suggest that this interaction might explain the mutant's selective advantage by means of repression of stem cell differentiation signals. Repression of STAT3 activity by cyclin D1 might also play a previously unrecognized role in providing a germline-selective advantage to spermatogonia for the recurrent mutations in the receptor tyrosine kinases that cause Apert syndrome and MEN2B. Looking at recurrent mutations driven by germline selection in different gene families can help highlight common causal signaling pathways.
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