OA04.03 Mobocertinib in NSCLC With EGFR Exon 20 Insertions: Results From EXCLAIM and Pooled Platinum-Pretreated Patient Populations

The aim of this study was to characterize and identify causative polymorphisms in the leptin receptor (LEPR) gene responsible for the seasonal variation of reproductive traits in sheep. Three reproductive seasonality traits were studied: the total days of anoestrous (TDA), the progesterone cycling months (P4CM) and the oestrous cycling months (OCM). In total, 18 SNPs were detected in 33 ewes with extreme values for TDA and OCM. Six SNPs were non-synonymous substitutions and two of them were predicted in silico as deleterious: rs596133197 and rs403578195. These polymorphisms were then validated in 239 ewes. The SNP rs403578195, located in exon 8 and leading to a change of alanine to glycine (Ala284Gly) in the extracellular domain of the protein, was associated with the OCM trait, being the G allele associated with a decrease of 12 percent of the OCM trait. Haplotype analyses also suggested the involvement of other non-synonymous SNP located in exon 20 (rs405459906). This SNP also produces an amino acid change (Lys1069Glu) in the intracellular domain of the protein and segregates independently of rs403578195. These results confirm for the first time the role of the LEPR gene in sheep reproductive seasonality.

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Molecular Analysis of Targeted Insecticide Resistance Gene Mutations in Field-Caught Mosquitos of Medical Importance From Saudi Arabia

Journal of Medical Entomology ◽

10.1093/jme/tjab048 ◽

2021 ◽

Author(s):

Yuan Fang ◽

Ernest Tambo ◽

Jing-Bo Xue ◽

Yi Zhang ◽

Xiao-Nong Zhou ◽

...

Keyword(s):

Saudi Arabia ◽

Insecticide Resistance ◽

Resistance Gene ◽

Phylogenetic Analyses ◽

Gene Mutations ◽

Mosquito Vector ◽

Dengue Disease ◽

The Status ◽

History Of ◽

Exon 20

Abstract Gene mutations on target sites can be a valuable indicator of the status of insecticide resistance. Jeddah, a global commercial and major port-of-entry city, is bearing the brunt of dengue disease burden in Saudi Arabia. In the current study, six genotypes of three codon combinations (989, 1016, and 1534) were observed on voltage-gated sodium channel (VGSC) gene in Jeddah’s Aedes aegypti population, with PGF/PGC as the dominant one. Two types of introns between exon 20 and 21 on VGSC have been identified for the first time in Ae. aegypti in Saudi Arabia. Statistical and phylogenetic analyses showed that the intron type was significantly associated with the 1016 allele and may reflect the history of insecticide treatment in different continents. In addition, fixation of the L1014F allele on VGSC and G119S on acetylcholinesterase 1 gene was detected in local Culex quinquefasciatus populations, with frequencies of 95.24 and 100%, respectively. To the best of our knowledge, this is the first report of resistant-associated mutations in field-caught Cx. quinquefasciatus in Saudi Arabia. The high prevalence of insecticide resistance gene mutations in local primary mosquito vector species highlights the urgent need to carry out comprehensive insecticide resistance surveillance in Saudi Arabia.

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P76.43 Co-occurring genomic alterations and treatment outcomes in patients with EGFR exon 20 insertion positive NSCLC

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2021.01.1100 ◽

2021 ◽

Vol 16 (3) ◽

pp. S605-S606

Author(s):

G. Bravo Montenegro ◽

A. Vanderwalde ◽

L. Raez ◽

J. Nieva ◽

R. Feldman ◽

...

Keyword(s):

Treatment Outcomes ◽

Genomic Alterations ◽

Exon 20

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Extensive functional evaluation of exon 20 insertion mutations of EGFR

Lung Cancer ◽

10.1016/j.lungcan.2020.12.023 ◽

2021 ◽

Vol 152 ◽

pp. 135-142

Author(s):

Takeshi Hirose ◽

Masachika Ikegami ◽

Makoto Endo ◽

Yoshihiro Matsumoto ◽

Yasuharu Nakashima ◽

...

Keyword(s):

Functional Evaluation ◽

Exon 20 ◽

Insertion Mutations

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Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia

Nature Communications ◽

10.1038/s41467-021-24705-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Masahiko Ajiro ◽

Tomonari Awaya ◽

Young Jin Kim ◽

Kei Iida ◽

Masatsugu Denawa ◽

...

Keyword(s):

Small Molecule ◽

Genetic Disease ◽

Therapeutic Strategy ◽

Therapeutic Potential ◽

Familial Dysautonomia ◽

Therapeutic Modality ◽

Aberrant Splicing ◽

Intronic Splicing Enhancer ◽

Exon 20 ◽

Splicing Enhancer

AbstractApproximately half of genetic disease-associated mutations cause aberrant splicing. However, a widely applicable therapeutic strategy to splicing diseases is yet to be developed. Here, we analyze the mechanism whereby IKBKAP-familial dysautonomia (FD) exon 20 inclusion is specifically promoted by a small molecule splice modulator, RECTAS, even though IKBKAP-FD exon 20 has a suboptimal 5′ splice site due to the IVS20 + 6 T > C mutation. Knockdown experiments reveal that exon 20 inclusion is suppressed in the absence of serine/arginine-rich splicing factor 6 (SRSF6) binding to an intronic splicing enhancer in intron 20. We show that RECTAS directly interacts with CDC-like kinases (CLKs) and enhances SRSF6 phosphorylation. Consistently, exon 20 splicing is bidirectionally manipulated by targeting cellular CLK activity with RECTAS versus CLK inhibitors. The therapeutic potential of RECTAS is validated in multiple FD disease models. Our study indicates that small synthetic molecules affecting phosphorylation state of SRSFs is available as a new therapeutic modality for mechanism-oriented precision medicine of splicing diseases.

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