Department of Molecular Endocrinology, Fujii Memorial Institute of Medical Sciences, Tokushima University, Tokushima, Japan; Research and Innovation Liaison Office, Institute for Advanced Medical Sciences, Tokushima University, Tokushima, Japan.
Department of Molecular Endocrinology, Fujii Memorial Institute of Medical Sciences, Tokushima University, Tokushima, Japan; Department of Endocrinology and Diabetes Mellitus, Fukuoka University School of Medicine, Fukuoka, Japan.
Bone. 2024 May;182:117057. doi: 10.1016/j.bone.2024.117057. Epub 2024 Feb 25.
Excessive actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia. It is possible that there still remain unknown causes or mechanisms for FGF23-related hypophosphatemic diseases. We report two male cousins who had been suffering form FGF23-related hypophosphatemic osteomalacia. Sequencing of exons and exon-intron junctions of known causative genes for FGF23-related hypophosphatemic diseases and whole genome sequencing were conducted. Luciferase assay was used to evaluate the effect of a detected nucleotide change on mRNA stability. Two cousins showed hypophosphatemia with impaired proximal tubular phosphate reabsorption and high FGF23. Serum phosphate of their mothers was within the reference range. Exome sequencing of the proband detected no mutations. Whole genome sequencing of the patients and their mothers identified a nucleotide change in the 3'-UTR of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) gene (c.*1280_*1287dupGTGTGTGT) which is heterozygous in the mothers and hemizygous in the patients. While sixteen is the most prevalent number of GT repeats, this family had twenty repeats. Luciferase assay indicated that mRNA with 3'-UTR of PHEX with 20 GT repeats was more unstable than that with 16 repeats. Sequencing of exons and exon-intron junctions of known causative genes for FGF23-related hypophosphatemic diseases cannot identify all the genetic causes. Our results strongly suggest that changes of PHEX expression by a nucleotide change in the 3'-UTR is a novel mechanism of FGF23-related hypophosphatemic osteomalacia.
FGF23 的过度作用可导致多种低磷性佝偻病/骨软化症。可能还有未知的原因或机制导致与 FGF23 相关的低磷血症性疾病。我们报告了两名患有 FGF23 相关低磷性骨软化症的男性表兄弟。对已知导致 FGF23 相关低磷血症疾病的基因的外显子和外显子-内含子接头进行了测序，以及进行了全基因组测序。采用荧光素酶报告基因检测来评估检测到的核苷酸变化对 mRNA 稳定性的影响。两名表兄弟均表现为低磷血症，近端肾小管磷重吸收受损，FGF23 水平升高。他们母亲的血清磷在参考范围内。先证者的外显子组测序未发现突变。对患者及其母亲进行全基因组测序，发现了一个与 X 染色体上的内肽酶同源的磷酸盐调节基因（PHEX）基因的 3'UTR 中的核苷酸变化（c.*1280_*1287dupGTGTGTGT），该突变在母亲中为杂合子，在患者中为半合子。虽然十六个 GT 重复是最常见的，但这个家族有二十个重复。荧光素酶报告基因检测表明，PHEX 基因 3'UTR 有 20 个 GT 重复的 mRNA 比有 16 个重复的 mRNA 更不稳定。对已知导致 FGF23 相关低磷血症疾病的基因的外显子和外显子-内含子接头进行测序不能确定所有的遗传原因。我们的研究结果强烈表明，3'UTR 中核苷酸变化引起的 PHEX 表达改变是 FGF23 相关低磷性骨软化症的一种新机制。
