Biology subjects

Lyon, G.

Publications and source records attributed to Lyon, G..

3 recordsLinked to original sources

bioRxiv2024

A repository of Ogden syndrome (NAA10) and NAA15 patient derived iPSC lines and isogenic pairs by X-chromosome screening and genome-editing.

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting 80% of cytosolic proteins in humans. The human essential gene, NAA10, encodes the enzyme NAA10, as the catalytic subunit for the N-terminal acetyltransferase A (NatA) complex, including the accessory protein, NAA15. The first human disease directly involving NAA10 was discovered in 2011, and it was named Ogden syndrome (OS), after the location of the first affected family residing in Ogden, Utah, USA. Since that time, other variants have been found in NAA10 and NAA15. Here we describe the generation of 31 iPSC lines, with 16 from females and 15 from males. This cohort includes CRISPR-mediated correction to the wild-type genotype in 4 male lines, along with editing one female line to generate homozygous wild-type or mutant clones. Following the monoclonalizaiton and screening for X-chromosome activation status in female lines, 3 additional pairs of female lines, in which either the wild type allele is on the active X chromosome (Xa) or the pathogenic variant allele is on Xa, have been generated. Subsets of this cohort have been successfully used to make cardiomyocytes and neural progenitor cells (NPCs). These cell lines are made available to the community via the NYSCF Repository.

genetics↗

bioRxiv2023

Evaluating possible maternal effect lethality of Naa10 knockout mice, and modulation of phenotypes for embryonic and neonatal lethality by genetic background and environment

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/ymale mice on the inbred genetic background in this different animal facility.

genetics↗

bioRxiv2019

Phen2Gene: Rapid Phenotype-Driven Gene Prioritization for Rare Diseases

Human Phenotype Ontology (HPO) terms are increasingly used in diagnostic settings to aid in the characterization of patient phenotypes. The HPO annotation database is updated frequently and can provide detailed phenotype knowledge on various human diseases, and many HPO terms are now mapped to candidate causal genes with binary relationships. To further improve the genetic diagnosis of rare diseases, we incorporated these HPO annotations, gene-disease databases, and gene-gene databases in a probabilistic model to build a novel HPO-driven gene prioritization tool, Phen2Gene. Phen2Gene accesses a database built upon this information called the HPO2Gene Knowledgebase (H2GKB), which provides weighted and ranked gene lists for every HPO term. Phen2Gene is then able to access the H2GKB for patient-specific lists of HPO terms or PhenoPackets descriptions supported by GA4GH (http://phenopackets.org/), calculate a prioritized gene list based on a probabilistic model, and output gene-disease relationships with great accuracy. Phen2Gene outperforms existing gene prioritization tools in speed, and acts as a real-time phenotype driven gene prioritization tool to aid the clinical diagnosis of rare undiagnosed diseases. In addition to a command line tool released under the MIT license (https://github.com/WGLab/Phen2Gene), we also developed a web server and web service (https://phen2gene.wglab.org/) for running the tool via web interface or RESTful API queries. Finally, we have curated a large amount of benchmarking data for phenotype-to-gene tools involving 197 patients across 76 scientific articles and 85 patients de-identified HPO term data from CHOP.

bioinformatics↗