三木 隆司

Craniopharyngiomas, including adamantinomatous (ACP) and squamous papillary (PCP) types, are challenging to treat because of their proximity to crucial pituitary structures. This study aimed to characterize the cellular composition, tumor tissue diversity, and cell-cell interactions in ACPs and PCPs using single-cell RNA sequencing. Single-cell clustering revealed diverse cell types, further classified into developing epithelial, calcification, and immune response for ACP and developing epithelial, cell cycle, and immune response for PCP, based on gene expression patterns. Subclustering revealed the enrichment of classical M1 and M2 macrophages in ACP and PCP, respectively, with high expression of pro-inflammatory markers in classical M1 macrophages. The classical M1 and M2 macrophage ratio significantly correlated with the occurrence of diabetes insipidus and panhypopituitarism. Cell-cell interactions, particularly involving CD44-SPP, were identified between tumor cells. Thus, we developed a comprehensive cell atlas that elucidated the molecular characteristics and immune cell inter-networking in ACP and PCP tumor microenvironments.

Fructose-1,6-bisphosphatase (FBPase) deficiency, caused by an FBP1 mutation, is an autosomal recessive disorder characterized by hypoglycemic lactic acidosis. Due to the rarity of FBPase deficiency, the mechanism by which the mutations cause enzyme activity loss still remains unclear. Here we identify compound heterozygous missense mutations of FBP1, c.491G>A (p.G164D) and c.581T>C (p.F194S), in an adult patient with hypoglycemic lactic acidosis. The G164D and F194S FBP1 mutants exhibit decreased FBP1 protein expression and a loss of FBPase enzyme activity. The biochemical phenotypes of all previously reported FBP1 missense mutations in addition to G164D and F194S are classified into three functional categories. Type 1 mutations are located at pivotal residues in enzyme activity motifs and have no effects on protein expression. Type 2 mutations structurally cluster around the substrate binding pocket and are associated with decreased protein expression due to protein misfolding. Type 3 mutations are likely nonpathogenic. These findings demonstrate a key role of protein misfolding in mediating the pathogenesis of FBPase deficiency, particularly for Type 2 mutations. This study provides important insights that certain patients with Type 2 mutations may respond to chaperone molecules.