Study Of The Molecular Mechanism In Two X-linked Hypophosphatemic Rickets Pedigrees

Background and objectivesPhosphorus is a kind of important material involved in the composition of human body and can be found in all human cells. It is also an indispensable nutrition connected with the maintaining of the regular body growth. Hypophosphatemic rickets is a relatively rare metabolic bone disease characterized by mineralization disorder in new synthetic matrix. Hypophosphatemic rickets is mainly a kind of hereditary disease, and X-linked hypophosphatemic ricket (XLH) is the most common hereditary hypophosphatemic rickets. In 1937, Albright et al described the first case of hypophosphatemic rickets, and named it vitamin D resistant rickets.XLH is a kind of genetic disease characterized by hypophosphatemia and bone dysplasia caused by renal phosphorus reabsorption disorder. The incidence of XLH is high, and X-linked dominant hereditary disease is the most common type, which is mainly caused by PHEX gene mutation. The classic clinical performance characterizes include osteoporosis and bone abnormalities (such as bending of the lower extremities), muscle weakness, short stature, teeth dysplasia, bone pain, multiple fracture, etc. The main biochemical traits of this disease are hypophosphatemia, normal serum calcium level with hypocalciuria, normal or low serum 1,25-(OH)2D3 level, normal serum PTH level and increased ALP(alkaline phosphatase activity). The definite diagnosis of XLH depends on gene detection to find the genetic mutation site. At present, the main treatment of XLH is through oral phosphate and vitamin D, and surgical correction for skeletal deformities, however these therapy only can partially improve the skeletal deformities and promote bone growth, while in some patients, these methods are not effective. Therefore, the research on the mechanism of XLHR has important clinical significance on the treatment of the patients. In our study, we will perform genetic detect and mutation diagnosis on PHEX gene in two cases of family XLHR pedigree to find the related gene mutation point, at the same time, we will also investigate the pathogenesis of this disease to provide more material for the future clinical research and treatment of this disease, in order to help the clinicians get better understand in this disease.Subjects and methodsTwo clinical suspected XLHR families were identified and screened for mutation site in PHEX gene. The pathogenesis of XLHR was also discussed in this study.ResultsThe probands of these two XLHR families were both characterized by arcuate deformities of lower extremities, short stature; and proband A also suffered from joint intumescence, bone pain, fracture, fatigue and other symptoms. Biochemical examination displayed that the blood phosphorus level of the two probands were lower, the serum calcium was normal or lower, the serum 1.25-(OH)2D3 level was normal (in the normal lower limit) and the PTH level was normal. The parents of the two probands were all not close relatives, and the mother of the proband A also showed the same symptom. The PHEX gene detection of proband A revealed a homozygotic mutation identified in the PHEX gene, and this mutation was located at the EXON 12 of PHEX gene(c.1363 C＞T). This was predicted to cause the mutation between glutamic acid (Glu) and stop codon at the 455 amino acid in PHEX protein (p.E455X). At the same time, the mother of the proband also showed the same mutation at the same site, but the mutation is heterozygote. While the PHEX gene detection of proband B showed another mutation at the EXON 3 of PHEX gene (c.200 T>G), which was heterozygote and could lead to the mutation between leucine (Leu) and stop codon at the 67 amino acid in PHEX gene (p.L67X). Both of the two mutations were predicted to cause PHEX protein premature, thus affecting its enzyme activity. The probands and the mother of proband A were all treated by supplement of oral phosphorus and vitamin D. and we also performed a 1 year follow-up, which displayed that the symptoms of the patients were improved.ConclusionIn this study, two different PHEX gene mutations were found in the PHEX gene of the two families, respectively, and are all dominant inherited. The mutations are predicted to be the pathogenesis of XLHR in the two families.SignificanceIn our study, we has not only made a definite diagnosis on the two families, but also investigated the potential pathogenesis of this disease, which may provide more significant data for clinical research and treatment, in order to help the clinicians get better understand on XLHR.