Rauen, K. A. | Search bioRxiv

bioRxiv2022

Cross-species analysis of LZTR1 loss-of-function mutants demonstrates dependency to RIT1 orthologs

RAS GTPases are highly conserved proteins involved in the regulation of mitogenic signaling. We have previously described a novel Cullin 3 RING E3 ubiquitin ligase complex formed by the substrate adaptor protein LZTR1 that binds, ubiquitinates, and promotes proteasomal degradation of the RAS GTPase RIT1. In addition, others have described that this complex is also responsible for the ubiquitination of canonical RAS GTPases. Here, we have analyzed the phenotypes of LZTR1 loss-of-function mutants in both fruit flies and mice and have demonstrated biochemical dependency on their RIT1 orthologs. Moreover, we show that LZTR1 is haplosufficient in mice and that embryonic lethality of the homozygous null allele can be rescued by deletion of RIT1.

genetics↗

bioRxiv2018

Assessing the Gene-Disease Association of 19 Genes with the RASopathies using the ClinGen Gene Curation Framework

The RASopathies are a complex group of diseases regarding phenotype and genetic etiology. The ClinGen RASopathy Expert Panel assessed published and other publicly available evidence supporting the association of 19 genes with RASopathy conditions. Using the semi-quantitative literature curation method developed by the ClinGen Gene Curation Working Group, evidence for each gene was curated and scored for Noonan syndrome, Costello syndrome, cardiofaciocutaneous (CFC) syndrome, Noonan syndrome with multiple lentigines (NSML), and Noonan-like syndrome with loose anagen hair (NS/LAH).\n\nThe curated evidence supporting each gene-disease relationship was then discussed and approved by the ClinGen RASopathy Expert Panel. Each associations strength was classified as Definitive, Strong, Moderate, Limited, Disputed, or No Evidence. Eleven genes were classified as definitively associated with at least one RASopathy condition. Two genes classified as strong for association with at least one RASopathy condition while one gene was moderate and three were limited. The RAS EP also refuted the association of two genes for a RASopathy condition. Overall, our results provide a greater understanding of the different gene-disease relationships within the RASopathies and can help guide and direct clinicians, patients and researchers who are identifying variants in individuals with a suspected RASopathy\n\nGRANT NUMBERSResearch reported in this publication was supported by the National Human Genome Research Institute (NHGRI) under award number U41HG006834. MZ received support from German Federal Ministry of Education and Research (BMBF): NSEuroNet (FKZ 01GM1602A), GeNeRARe (FKZ 01GM1519A).

genetics↗