Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: DrugBank:EXPT01586 (
G418
)
2,237
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Hirschsprung disease (HSCR) is a genetic disorder characterized by the absence of ganglion cells in the gut.
RET
is considered to be the main susceptibility gene. In our previous screening of 83 HSCR patients, targeted exome sequencing identified nine rare variants of
RET
, most of which were new discoveries. Here, we performed
in vitro
arrays with functional studies to investigate their effects. Two variants (p.R77C and p.R67insL) were demonstrated to disrupt the glycosylation of RET and affect its subcellular localization. Three nonsense mutations (p.W85X, p.E252X, and p.Y263X) could not produce detectable RET full-length protein, and the other three mutations (p.R770X, p.Q860X, and p.V778Afs*1) were translated into truncated proteins of predicted sizes. One canonical splice acceptor site mutation (c.2802-2 A > G) was verified to affect gene regulation through aberrant splicing. In addition, we explored the effects of read-through reagents on
RET
nonsense mutations and showed that
G418
significantly increased the full-length
RET protein
expression of p.Y263X in a dose-dependent manner, together with a mild recovery of p-ERK and p-STAT3. Our data provide a functional analysis of novel
RET
mutations and suggest that all of the rare variants detected from patients with clinically severe HSCR are indeed pathogenic. Thus, our findings have implications for proper genetic counseling.
...
PMID:Functional Studies on Novel
RET
Mutations and Their Implications for Genetic Counseling for Hirschsprung Disease. 3164 19
