Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome

Abstract

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 a-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.

Mutations in plasmalemma vesicle-associated protein cause severe syndromic protein-losing enteropathy

“…For two frameshift variants, rs144686314 and rs143864957, there are 151 and 19 homozygous carriers in ExAC, respectively. Vissers et al hypothesised a dominant, activating effect of de novo missense variants in A2ML1 as the underlying mechanism, which might lead to Noonan syndrome in their patients 5. We deem it unlikely that the observed homozygous stop variant in our patient was responsible for the observed phenotype and the ACMG guidelines3 classify it as a variant of unknown significance.…”

“…Two were premature stop mutations in A2ML1 and PLVAP. A2ML1 codes for alpha-2-macroglobulin-like 1 and has been discussed in the context of Noonan syndrome, but all variants were classified as variants of unknown significance because their contribution to Noonan syndrome could not be confirmed 5. Copy number variants and heterozygous rare variants in A2ML1 have also been described to be associated with otitis media in children 6.…”

Exploring the intrinsic differences among breast tumor subtypes defined using immunohistochemistry markers based on the decision tree

“…A2ML1, which encodes the secreted protease inhibitor α-2-macroglobulin (A2M)-like-1, activates mutations in signal transducers of the RAS/mitogen-activated protein kinase (MAPK) pathway34. FZD9 19 encodes WNT receptors and is an important factor affecting WNT signaling.…”

Recent advances in RASopathies

“…Vissers et al 43 performed trio exome sequencing and identified a de novo variant (p.R802H) of A2ML1 in an individual with NS. Additional analyses of 155 individuals revealed missense variants (p.R592L and p.R802L) of A2ML1 in two families with NS.…”