ABSTRACT
Loss-of-function mutations in CYP24A1 (MIM 126065 20q13.2), the gene encoding the 24-hydroxylase responsible for 25-OH-D and 1,25-(OH)2D degradation, are identified in about 20% of patients presenting Idiopathic Infantile Hypercalcemia (IIH) (MIM 143880). Common features of this autosomal recessive condition included hypercalcemia with hypercalciuria, suppressed PTH and a high 25-OH-D3:24,25-(OH)2D3 ratio. Medical care mainly relies on sun protection and life-long contraindication of vitamin D to avoid complications such as early nephrocalcinosis and renal failure. Molecular diagnosis therefore keeps a crucial place in the diagnosis of IIH, and genetic counseling should be systematically recommended to prevent vitamin D administration in affected siblings. In this report is described the molecular characterization of a CYP24A1 deletion identified in two unrelated families. This highlights the potential role of CYP24A1 copy number variations (CNV) in IIH. Considering the presence of CNV affecting CYP24A1 in public databases, CNV analysis should be systematically added to the sequencing studies in IIH. Targeted Massively Parallel Sequencing (MPS) study coupled with a CNV detection tool called CovCop is a powerful method to detect genic rearrangement and improve genetic analysis.
Subject(s)
Hypercalcemia/diagnosis , Hypercalcemia/genetics , Infant, Newborn, Diseases/diagnosis , Infant, Newborn, Diseases/genetics , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/genetics , Pathology, Molecular , Vitamin D3 24-Hydroxylase/genetics , Adolescent , Child , Child, Preschool , DNA Copy Number Variations/genetics , Female , Humans , Hypercalcemia/drug therapy , Hypercalcemia/pathology , Infant , Infant, Newborn, Diseases/drug therapy , Infant, Newborn, Diseases/pathology , Loss of Function Mutation/genetics , Male , Metabolism, Inborn Errors/drug therapy , Metabolism, Inborn Errors/pathology , Nephrocalcinosis/drug therapy , Nephrocalcinosis/genetics , Nephrocalcinosis/prevention & control , Renal Insufficiency/drug therapy , Renal Insufficiency/genetics , Renal Insufficiency/prevention & control , Sequence Deletion/genetics , Vitamin D/therapeutic useABSTRACT
5-HT6 Receptors are relatively recently discovered receptors that interact with cholinergic, glutamatergic, GABAergic and dopaminergic transmission systems. These receptors have been implicated in the CNS system as therapeutic targets in applications such as psychosis, reduction of body weight or Alzheimer's disease. As part of our efforts to develop 5-HT6 antagonists, we explored the benzothiazolone scaffold substituted in position 3 or 6 respectively with ethylamino chains and an aromatic ring connected through a sulfonyl linker. Final compounds were evaluated in radioligand binding assays for their ability to interact with 5-HT6 receptors. Their potential cytotoxic effects were determined on the human neuroblastoma cell line SY5Y. They showed very low cytotoxicity, and one of them has submicromolar affinity for 5-HT6 receptors.
