Hypertriglyceridemia-Induced Acute Pancreatitis Exacerbated by Combined Oral Contraceptive Use: A Case Report.

Acute pancreatitis can be induced by a vast variety of etiologies including its more common causes such as cholelithiasis and alcohol abuse, but in certain cases it can also be secondary to hypertriglyceridemia. Additionally, combined oral contraceptive use can enhance the severity of hypertriglyceridemia-induced acute pancreatitis (HTG-AP). The data between this association is much more limited than the more common causes of acute pancreatitis. In this case, we aim to highlight the onset of hypertriglyceridemia-induced acute pancreatitis due to recent combined oral contraceptive use in a 34-year-old Hispanic female patient with a family history of hypertriglyceridemia. With the initiation of a low-fat diet, insulin regimen, and lipid-lowering medications, she was able to significantly improve her elevated triglyceride levels from 3772 to 440 throughout the duration of her six-day hospital stay. Due to the less commonly known relationship between combined oral contraceptive use and HTG-AP, this case serves to enhance understanding of the pathophysiology of this condition, the appropriate diagnostic evaluation, and the associated treatment options to optimize patient care and create efficacious management plans. By increasing awareness of this association, patients with familial hypertriglyceridemia can be made aware of the risks of combined oral contraceptive use to accordingly prevent complications and improve clinical outcomes.

Genetic compensation in a stable slc25a46 mutant zebrafish: A case for using F0 CRISPR mutagenesis to study phenotypes caused by inherited disease.

A phenomenon of genetic compensation is commonly observed when an organism with a disease-bearing mutation shows incomplete penetrance of the disease phenotype. Such incomplete phenotypic penetrance, or genetic compensation, is more commonly found in stable knockout models, rather than transient knockdown models. As such, these incidents present a challenge for the disease modeling field, although a deeper understanding of genetic compensation may also hold the key for novel therapeutic interventions. In our study we created a knockout model of slc25a46 gene, which is a recently discovered important player in mitochondrial dynamics, and deleterious mutations in which are known to cause peripheral neuropathy, optic atrophy and cerebellar ataxia. We report a case of genetic compensation in a stable slc25a46 homozygous zebrafish mutant (hereafter referred as "mutant"), in contrast to a penetrant disease phenotype in the first generation (F0) slc25a46 mosaic mutant (hereafter referred as "crispant"), generated with CRISPR/Cas-9 technology. We show that the crispant phenotype is specific and rescuable. By performing mRNA sequencing, we define significant changes in slc25a46 mutant's gene expression profile, which are largely absent in crispants. We find that among the most significantly altered mRNAs, anxa6 gene stands out as a functionally relevant player in mitochondrial dynamics. We also find that our genetic compensation case does not arise from mechanisms driven by mutant mRNA decay. Our study contributes to the growing evidence of the genetic compensation phenomenon and presents novel insights about Slc25a46 function. Furthermore, our study provides the evidence for the efficiency of F0 CRISPR screens for disease candidate genes, which may be used to advance the field of functional genetics.