Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.
Level 5 - mechanism / opinion, no new human data
In vitro bench and biochemical assays on cells from a single patient.
PubMed 31249027 · doi:10.1042/BCJ20190294
What was done
Primary dermal fibroblasts and red blood cells from a 3-year-old patient with a de novo heterozygous ODC1 mutation (c.1342 A>T) were compared against neonatal and adult control fibroblasts. Researchers measured ODC protein accumulation, putrescine levels, and ODC catalytic activity via a 14C radioactive assay, and tested the cellular effects of in vitro treatment with the ODC inhibitor alpha-difluoromethylornithine (DFMO).
What was found
Patient dermal fibroblasts showed elevated ODC protein and putrescine accumulation compared to controls. ODC catalytic activity was 12- to 17-fold higher in patient fibroblasts and 125- to 137-fold higher in patient red blood cells relative to controls. In vitro exposure to DFMO reduced ODC activity and putrescine to control levels in patient fibroblasts without adversely altering cell morphology or inducing cell death.
Why it matters
This study delineates the biochemical mechanism of a rare ODC1 gain-of-function disorder and provides preclinical in vitro rationale for repurposing DFMO to normalize polyamine dysregulation.
Limits
The study is limited to laboratory bench assays on primary cells from a single patient (n = 1). The abstract reports no clinical efficacy, safety, or dosing data in vivo.
Cited by
- supports Bachmann-Bupp syndrome is caused by a genetic mutation that results in elevated levels of the enzyme ODC1.