Nuclear factor one A (NFIA) is a transcription factor that regulates the development of the central nervous system. Haploinsufficiency of the NFIA gene causes NFIArelated disorder, which includes brain abnormalities and intellectual disability, with or without urinary tract defects. Intragenic deletions, nonsense variants, frameshift variants, and missense variants in one allele of the NFIA gene have been reported to cause various neurological and urogenital symptoms. Here we report a 10-year-old male patient with developmental delay, coarctation of the aorta, and distinctive facial features. Exome analysis identified a rare de novo heterozygous missense variant p. Thr395Met in NFIA. We employed zebrafish as a model organism in our NFIA analysis and found that nfia À/À zebrafish initially showed a loss of commissural axons in the brain, and eventually underwent growth retardation resulting in premature death.Impairment of the commissural neurons in nfia À/À zebrafish embryos could be restored by the expression of wild-type human NFIA protein, but not of mutant human protein harboring the p.Thr395Met substitution, indicating that this variant affects the function of NFIA protein. Taken together, we suggest that the p.Thr395Met allele in the NFIA gene is relevant to the pathogenesis of NFIA-related disorder.

The klotho gene encodes a transmembrane protein αKlotho that interacts with a fibroblast growth factor (FGF) receptor in renal tubular epithelial cells and functions as a co-receptor for FGF23, which is an osteocytes-derived hormone. This bone-to-kidney signal promotes urinary phosphate excretion. Interestingly, αKlotho knockout mice show an accelerated aging and a shortened life span. Similarly, C. elegans lacking the αklotho homologue showed a short life span. However, the physiological basis of aging-related function of αklotho remain unclear. The αklotho-deficient vertebrate animals other than mice have been awaited as an alternative model of premature aging. We here employed zebrafish in our study and revealed that αklotho mutant zebrafish appeared to be normal at 3 months postfertilization (mpf) but eventually underwent premature death by 9 mpf, while normal zebrafish is known to survive for 42 months. We also assessed the motor ability of zebrafish in a forced swimming assay and found that αklotho mutant zebrafish displayed reduced swimming performance before their survival declined. A recent study also reported a similar finding that αklotho-deficient zebrafish exhibited a short life span and reduced spontaneous movements. Taken together, these results suggest that αKlotho mutant zebrafish show premature aging and are useful to investigate aging in vertebrates.

No abstract

The klotho gene encodes a transmembrane protein aKlotho that interacts with a fibroblast growth factor receptor in renal tubular epithelial cells and functions as a co-receptor for FGF23, which is an osteocytes-derived hormone. It is known that this bone-to-kidney signal promotes urinary phosphate excretion. Interestingly, aKlotho-deficient mice show accelerated aging and shortened life span in addition to dysregulation of serum phosphorus. However, physiological basis of aging-related function of aklotho and its generality in animals remain unclear. The aklotho-deficient vertebrate animals other than mice have been awaited as an alternative premature aging model. We here employed zebrafish in our aklotho study and revealed that aklotho mutant zebrafish appear to be normal at 3 months postfertilization (mpf) in young adults but eventually undergo premature death by 9 mpf, while normal zebrafish is known to survive for 42 months. We also assessed motor ability of zebrafish in a forced swimming assay and found that aklotho mutant zebrafish displayed reduced swimming performance before their survival declined. A recent study also reported a similar finding that aklotho-deficient zebrafish exhibited short life span and reduced spontaneous movements. Taken together, these results suggest that aKlotho mutant zebrafish show premature aging and are useful to investigate aging in vertebrates.