Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome
Open accessAbstract
Noonan syndrome (NS) is a developmental disorder characterized by short stature, facial dysmorphisms and congenital heart defects. To date, all mutations known to cause NS are dominant, activating mutations in signal transducers of the RAS/mitogen-activated protein kinase (MAPK) pathway. In 25% of cases, however, the genetic cause of NS remains elusive, suggesting that factors other than those involved in the canonical RAS/MAPK pathway may also have a role. Here, we used family-based whole exome sequencing of a case-parent trio and identified a de novo mutation, p.(Arg802His), in A2ML1, which encodes the secreted protease inhibitor α-2-macroglobulin (A2M)-like-1. Subsequent resequencing of A2ML1 in 155 cases with a clinical diagnosis of NS led to the identification of additional mutations in two families, p.(Arg802Leu) and p.(Arg592Leu). Functional characterization of these human A2ML1 mutations in zebrafish showed NS-like developmental defects, including a broad head, blunted face and cardiac malformations. Using the crystal structure of A2M, which is highly homologous to A2ML1, we identified the intramolecular interaction partner of p.Arg802. Mutation of this residue, p.Glu906, induced similar developmental defects in zebrafish, strengthening our conclusion that mutations in A2ML1 cause a disorder clinically related to NS. This is the first report of the involvement of an extracellular factor in a disorder clinically related to RASopathies, providing potential new leads for better understanding of the molecular basis of this family of developmental diseases.
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The rs73038782 variant in the A2ML1 host gene is enriched in black non-Hispanics from multiplex families without ID [33].
“Finally, the rs73038782 variant in the A2ML1 host gene, an inhibitor of various proteases and linked with some cases of Noonan syndrome, is enriched in black non-Hispanics from multiplex families without ID [33].”
From Enrichment of a subset of Neanderthal polymorphisms in autistic probands and siblings (2024) · cites this paper as [33]
The Discussion identifies A2ML1 as a protease inhibitor, and the paper reports A2ML1 mutations in people with Noonan-like features. But the Exome sequencing section discusses a different variant designation in a Noonan-syndrome case; our copy does not identify rs73038782 or report its enrichment in black non-Hispanics from multiplex families without intellectual disability (searched: rs73038782 and the population and family terms). (LLM, conf=0.87)
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- Authors
- Vissers, L. E., Bonetti, M., Paardekooper Overman, J., Nillesen, W. M., Frints, S. G. M., de Ligt, J., Zampino, G., Justino, A., Machado, J. C., Schepens, M., Brunner, H. G., Veltman, J. A., Scheffer, H., Gros, P., Costa, J. L., Tartaglia, M., van der Burgt, I., Yntema, H. G., & den Hertog, J.
- Affiliations
- Radboud University Nijmegen (NL)
- University Medical Center Utrecht (NL)
- Radboud University Medical Center (NL)
- Maastricht University Medical Centre (NL)
- Università Cattolica del Sacro Cuore (IT)
- Universidade do Porto (PT)
- Utrecht University (NL)
- Istituto Superiore di Sanità (IT)
- Corresponding author
- Yntema, Helger G
- ORCID
- Venue
- European Journal of Human Genetics
- Published
- 2014-06-18
- Volume
- 23
- Issue
- 3
- Pages
- 317-324
- ISSN
- 1018-4813 (ISSN-L)
- 1476-5438
- PMC
- PMC4326711
- OpenAlex
- W2016442156
- Cited by
- 75
- References
- 26
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 11 · 2023: 3 · 2022: 7 · 2021: 3 · 2020: 8 · 2019: 8 · 2018: 9 · 2017: 8 · 2016: 12 · 2015: 4
- FWCI
- 3.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- European Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, other-oa)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Ministerio de Economía y Competitividad
- Fundação para a Ciência e a Tecnologia (PTDC/BIM-MEC/0650/2012)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Noonan syndrome, germline mutations, RASopathies, de novo mutations, protease inhibitors, zebrafish model, cardiac anomalies, craniofacial dysmorphism, RAS/MAPK pathway, extracellular factors
- MeSH terms
- alpha-Macroglobulins, Animals, DNA Mutational Analysis, Female, Heterozygote, Humans, Male, Models, Molecular, Mutation, Noonan Syndrome, Pedigree, Phenotype, Protein Conformation, Zebrafish, Gene Expression, Germ-Line Mutation, Facies, Amino Acid Substitution, High-Throughput Nucleotide Sequencing, Exome
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