Extended mutational analyses of <i>FGFR1</i> in osteoglophonic dysplasia

Farrow, Emily; Davis, Siobhan I.; Mooney, Sean D.; Beighton, Peter; Mascarenhas, Leo; Gutierrez, Yvonne R.; Pitukcheewanont, Pisit; White, Kenneth E.

doi:10.1002/ajmg.a.31106

Cited by 50 publications

(41 citation statements)

References 16 publications

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“…However, the mutations leading to these disorders are located between the second and third putative Ig domains of FGFR1, just like mutations in FGFR2 and in FGFR3 that cause Crouzon syndrome, and hypo-or achondrodysplasia, respectively; note that patients affected by these other disorders do not develop hypophosphatemia. Surprisingly, some patients with OGD were reported to have elevated FGF23 levels [59,60]. This could indicate that the skeletal lesions develop because the constitutive activation of the FGFR1 leads to an up-regulation of FGF23 secretion in the metaphyseal growth plate and consequently renal phosphatewasting.…”

Section: Othersmentioning

confidence: 97%

“…White et al recently identified several different heterozygous missense mutations in FGFR1 that are all located within or close to the receptor's membranespanning domain. These mutations all affect amino acid residues that are highly conserved across species and seem to lead to constitutive receptor activation [59,60]. Heterozygous activating FGFR1 mutations are found in a patient with Pfeiffer syndrome [61] and in a case with the skeletal findings of Jackson-Weiss syndrome [62].…”

Section: Othersmentioning

confidence: 99%

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Inherited hypophosphatemic disorders in children and the evolving mechanisms of phosphate regulation

Baştepe

Jüppner

2008

Rev Endocr Metab Disord

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Phosphorous is essential for multiple cellular functions and constitutes an important mineral in bone. Hypophosphatemia in children leads to rickets resulting in abnormal growth and often skeletal deformities. Among various causes of low serum phosphorous are inherited disorders associated with increased urinary excretion of phosphate, including autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemia (XLH), autosomal recessive hypophosphatemia (ARHP), and hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Recent genetic analyses and subsequent biochemical and animal studies have revealed several novel molecules that appear to play key roles in the regulation of renal phosphate handling. These include a protein with abundant expression in bone, fibroblast growth factor 23 (FGF23), which has proven to be a circulating hormone that inhibits tubular reabsorption of phosphate in the kidney. Two other bone-specific proteins, PHEX and dentin matrix protein 1 (DMP1), appear to be necessary for limiting the expression of fibroblast growth factor 23, thereby allowing sufficient renal conservation of phosphate. This review focuses on the clinical, biochemical, and genetic features of inherited hypophosphatemic disorders, and presents the current understanding of hormonal and molecular mechanisms that govern phosphorous homeostasis.

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Section: Othersmentioning

confidence: 97%

Section: Othersmentioning

confidence: 99%

Inherited hypophosphatemic disorders in children and the evolving mechanisms of phosphate regulation

Baştepe

Jüppner

2008

Rev Endocr Metab Disord

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“…Recently, White et al identified several heterozygous missense mutations in fibroblast growth factor receptor 1 (FGFR1) (121). These mutations are in highly conserved residues comprising the extracellular (asparagine 330 to isoleucine, Asn330Ile) and transmembrane domains (tyrosine 374 to cysteine, Tyr374Cys; and cysteine 381 to arginine, Cys381Arg) of FGFR1, which seems to lead to constitutive receptor activation (122)(123). Hypophosphatemia, secondary to renal phosphate wasting associated with inappropriately normal 1,25(OH)2D3 levels, is present in affected individuals (124)(125).…”

Section: Osteoglophonic Dysplasia (Ogd)mentioning

confidence: 99%

FGF23 and Phosphate Wasting Disorders

2013

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A decade ago, only two hormones, parathyroid hormone and 1,25(OH)2D, were widely recognized to directly affect phosphate homeostasis. Since the discovery of fibroblast growth factor 23 (FGF23) in 2000 (1), our understanding of the mechanisms of phosphate homeostasis and of bone mineralization has grown exponentially. FGF23 is the link between intestine, bone, and kidney together in phosphate regulation. However, we still do not know the complex mechanism of phosphate homeostasis and bone mineralization. The physiological role of FGF23 is to regulate serum phosphate. Secreted mainly by osteocytes and osteoblasts in the skeleton (2-3), it modulates kidney handling of phosphate reabsorption and calcitriol production. Genetic and acquired abnormalities in FGF23 structure and metabolism cause conditions of either hyper-FGF23 or hypo-FGF23. Hyper-FGF23 is related to hypophosphatemia, while hypo-FGF23 is related to hyperphosphatemia. Both hyper-FGF23 and hypo-FGF23 are detrimentalto humans. In this review, we will discuss the pathophysiology of FGF23 and hyper-FGF23 related renal phosphate wasting disorders (4 IntroductionAccording to pathogenesis, ricketsis classified into calicopenic rickets, phosphopenicrickets, and a miscellaneous group associated with direct inhibitors of mineralization ( 5). In general, most instances of nutritional rickets are calicopenic, whereas heritable causes are usually phosphopenic. In this review we focus on hypophosphatemic rickets or osteomalacia. The causes of hypophosphatemia are various, of whichthe most prominent one is decreased reabsorption of phosphate in the proximal tubule.Although renal tubular disease can result in excessive renal phosphate wasting, in most hypophosphatemic disordersno abnormalities are found in the proximal tubule (6-7). It is speculated that an unknown factor is responsible for this phenomenon. The discovery of fibroblast growth factor 23 (FGF23), a member of the Phosphate homeostasisPhosphate comprises about 1% of total body weight. About 85% of total body phosphate resides in the bone, 14% in the cells, and only 1% in the serum and extracellular fluids. Maintenance of serum phosphate within its normal range allows for optimal mineralization of bone without deposition in vascular and other soft tissues. Serum phosphate concentration is determined Xianglan Huang et al. www.boneresearch.org | Bone Research 121by the balance among intestinal absorption of phosphate from the diet, its storage in bone, and its excretion in the urine. The proximal tubule is responsible for the reabsorption of phosphate filtered at the glomerulus and is the primary regulator of phosphate balance in the body. Transportation in the proximal tubule is driven primarily by sodium-potassium ATPase, which is located in the baso-lateral membrane of the cell (8-11). Under normal conditions, about 85% of the filtered phosphate is reabsorbed via the sodium-phosphate co-transporter (NaPi2a and NaPi2c) in the proximal tubule (9, 11). Parathyroid hormone (PTH) is one of the most potent horm...

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“…Features also include prominent supraorbital ridge, depressed nasal root, multiple unerupted teeth, diaphyseal fibrous lesions, and speech delay (Sklower Brooks et al, 1996). Mutations within FGFR1 are within the IgIII (also called D3) domain, the linker region and the initial transmembrane domain: N330I, Y374C, C381R (White et al, 2005;Farrow et al, 2006). They appear to be activating mutations, causing inappropriate dimerization of FGFR1.…”

Section: Notementioning

confidence: 99%