Publications by authors named "W Khalek"
Background: In European Union countries, any disease affecting less than 5 people in 10,000 is considered rare. As expertise is scarce and rare diseases (RD) are complex, RD patients can remain undiagnosed for many years. The period of searching for a diagnosis, called diagnostic delay, sometimes leads to a diagnostic dead end when the patient's disease is impossible to diagnose after undergoing all available investigations.
View Article and Find Full Text PDFBackground: Female genital mutilation is considered a crime but is still practiced today in Africa and the Middle East, despite all the laws that make this procedure illegal due to the long-term physical and psychological harm it causes to women. Millions of girls and women living today have undergone genital mutilation, which involves removing the external female genitalia either partially or totally, based on the belief that it restricts feminine sexuality, thereby "saving" a girl for marriage. For girls and women, the surgery offers no health advantages.
View Article and Find Full Text PDFCullin 3 (CUL3) is the scaffold of Cullin3 Ring E3-ligases (CRL3s), which use various BTB-adaptor proteins to ubiquitinate numerous substrates targeting their proteasomal degradation. mutations, responsible for a severe form of familial hyperkalemia and hypertension (FHHt), all result in a deletion of exon 9 (amino-acids 403-459) (CUL3-∆9). Surprisingly, while CUL3-∆9 is hyperneddylated, a post-translational modification that typically activates CRL complexes, it is unable to ubiquitinate its substrates.
View Article and Find Full Text PDFArticle Synopsis
- Gain-of-function mutations in the WNK1 and WNK4 genes cause familial hyperkalemic hypertension (FHHt), which leads to high blood pressure and elevated potassium levels along with metabolic acidosis.
- Recent research has identified new mutations in the WNK1 gene that affect its interaction with the KLHL3-CUL3 ubiquitin ligase complex, crucial for renal ion transport regulation.
- Functional studies and a CRISPR/Cas9 mouse model demonstrated that these mutations result in diminished ubiquitination of the kidney-specific KS-WNK1 isoform, leading to increased activation of renal ion transport pathways and altered potassium balance.
Background: Mutations in four genes, WNK lysine deficient protein kinase 1 and 4 ( and ), kelch like family member 3 (), or Cullin 3 (), can result in familial hyperkalemic hypertension (FHHt), a rare Mendelian form of human arterial hypertension. Although all mutations result in an increased abundance of WNK1 or WNK4, all FHHt-causing mutations, resulting in the skipping of exon 9, lead to a more severe phenotype.
Methods: We created and compared two mouse models, one expressing the mutant Cul3 protein ubiquitously () and the other specifically in vascular smooth muscle cells ().