Klotho Lacks an FGF23-Independent Role in Mineral Homeostasis

Andrukhova, Olena; Bayer, Jessica; Schüler, Christiane; Zeitz, Ute; Murali, Sathish Kumar; Ada, Sibel; Álvarez‐Pez, José M.; Smorodchenko, Alina; Erben, Reinhold G.

doi:10.1002/jbmr.3195

Cited by 33 publications

(27 citation statements)

References 60 publications

(107 reference statements)

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“…This leads to phosphate wasting, secondary hypophosphatemia, and low circulating 1,25(OH)2D3. This translates into hypophosphatemia and hypocalcemia or hypophosphatemic rickets in some RS patients [64,67,68].…”

Section: Discussionmentioning

confidence: 99%

Two Novel FAM20C Variants in a Family with Raine Syndrome

Hernández-Zavala

Cortés-Camacho

Palma‐Lara

et al. 2020

Genes

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Two siblings from a Mexican family who carried lethal Raine syndrome are presented. A newborn term male (case 1) and his 21 gestational week brother (case 2), with a similar osteosclerotic pattern: generalized osteosclerosis, which is more evident in facial bones and cranial base. Prenatal findings at 21 weeks and histopathological features for case 2 are described. A novel combination of biallelic FAM20C pathogenic variants were detected, a maternal cytosine duplication at position 456 and a paternal deletion of a cytosine in position 474 in exon 1, which change the reading frame with a premature termination at codon 207 and 185 respectively. These changes are in concordance with a negative detection of the protein in liver and kidney as shown in case 2. Necropsy showed absence of pancreatic Langerhans Islets, which are reported here for the first time. Corpus callosum absence is added to the few reported cases of brain defects in Raine syndrome. This report shows two new FAM20C variants not described previously, and negative protein detection in the liver and the kidney. We highlight that lethal Raine syndrome is well defined as early as 21 weeks, including mineralization defects and craniofacial features. Pancreas and brain defects found here in FAM20C deficiency extend the functional spectrum of this protein to previously unknown organs.

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Section: Discussionmentioning

confidence: 99%

Two Novel FAM20C Variants in a Family with Raine Syndrome

Hernández-Zavala

Cortés-Camacho

Palma‐Lara

et al. 2020

Genes

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“…30,77,78,80,83 FGF23 has extrarenal effects on the cardiovascular, central nervous, and immune systems and nonrenal cells, such as MSCs and human monocytes . The main physiological function of klotho for in vivo mineral homeostasis is achieved by its role as a coreceptor mediating FGF23 action . Our new data with hMSCs showed that there was a significant correlation for constitutive expression of membrane‐bound klotho ( r = 0.52, P = 0.019) and a statistical trend of positive correlation for expression of secreted klotho ( r = 0.42, P = 0.064) with eGFR in a cohort of subjects without kidney disease .…”

Section: Impact Of Renal Function and Ckd On Vitamin D Metabolism In mentioning

confidence: 90%

Chronic kidney disease and vitamin D metabolism in human bone marrow–derived MSCs

Zhou

Glowacki

2017

Annals of the New York Academy of Sciences

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Vitamin D that is synthesized in the skin or is ingested undergoes sequential steps of metabolic activation with a cascade of cytochrome P450 enzymatic hydroxylations in liver and kidney to produce 1α,25-dihydroxyvitamin D [1α,25(OH)2D]. There are many tissues that are able to synthesize 1α,25(OH)2D, but the biological significance of extrarenal hydroxylases is unresolved. Human marrow-derived mesenchymal stem cells (marrow stromal cells, hMSCs) give rise to osteoblasts, and their differentiation is stimulated by 1α,25(OH)2D. In addition to being targets of 1α,25(OH)2D, hMSCs can synthesize it; from those observations, we further examined the local autocrine/paracrine role of vitamin D metabolism in osteoblast differentiation. Research with hMSCs from well-characterized subjects provides an innovative opportunity to evaluate effects of clinical attributes on regulation of hMSCs. Like the renal 1α -hydroxylase, the enzyme in hMSCs is constitutively decreased with age and chronic kidney disease (CKD); both are regulated by PTH1-34, IGF-1, calcium, 1α,25(OH)2D, 25(OH)D, and FGF23. CKD is associated with impaired renal biosynthesis of 1α,25(OH)2D, low bone mass, and increased fracture risk. Studies with hMSCs from CKD patients or aged subjects indicate that circulating 25(OH)D may have an important role in osteoblast differentiation on vitamin D metabolism and action in hMSCs.

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“…The codependency of FGF23 and Klotho is supported by mouse genetic studies showing that Fgf23 -/and Kl -/mice are exact phenocopies, characterized by hyperphosphatemia, excess 1,25(OH) 2 D 3 , soft tissue calcifications, and early mortality (2,(27)(28)(29). The nonredundant phenotypes are further supported by the fact that Kl -/mice are refractory to FGF23 effects (30)(31)(32), and compound mutant Fgf23 and Kl have nonadditive effects (27,(30)(31)(32)(33).…”

Section: Introductionmentioning

confidence: 95%