Inherited disorders of calcium and phosphate metabolism

Abstract

Purpose of Review Inherited disorders of calcium and phosphate homeostasis have variable presentation and can cause significant morbidity. Understanding the mode of inheritance and pathophysiology of these conditions will help in the diagnosis and early institution of therapy. Recent Findings Identification of genetic mutations in human subjects and animal models has advanced our understanding of many inherited disorders of calcium and phosphate regulation. Identification of mutations of CaSR also has improved our understanding of hypocalcemic and hypercalcemic conditions. Mutations of Fgf23, Klotho and phosphate transporter genes have been identified as causes for disorders of phosphate metabolism. Summary Calcium and phosphate homeostasis is tightly regulated in a narrow range due to their vital role in many biological processes. Inherited disorders of calcium and phosphate metabolism though uncommon can have severe morbidity. Genetic counseling of the affected families is an important part of the follow up of these patients.

STIM1/ORAI1 Loss-of-Function and Gain-of-Function Mutations Inversely Impact on SOCE and Calcium Homeostasis and Cause Multi-Systemic Mirror Diseases

“…Calcium (Ca 2+ ) is an elemental factor regulating a multitude of metabolic processes, signaling pathways, and cellular functions in all tissues, and mediates muscle contraction, nerve conduction, hormone release, and blood coagulation. Consistently, normal tissue and organ physiology strictly depends on the precise control of Ca 2+ entry, storage, and release, while abnormal Ca 2+ homeostasis induces various rare and common disorders affecting skeletal muscle, heart, bones, brain, skin, or the immune and hormonal systems ( Peacock, 2010 ; Gattineni, 2014 ).…”

Convergent Signaling Pathways Regulate Parathyroid Hormone and Fibroblast Growth Factor-23 Action on NPT2A-mediated Phosphate Transport

“…Parathyroid hormone (PTH) 2 and FGF23 display two remarkable features: 1) PTH and FGF23 exhibit parallel inhibition of renal phosphate transport mediated by NPT2A (sodium-dependent phosphate transporter-2a) but opposing actions on 1,25(OH) 2 -vitamin D; 2) despite being structurally and functionally distinct classes of membrane-delimited receptors, PTH and FGF receptors activate kinases that obligatorily phosphorylate NHERF1 at conserved sites required for their phosphaturic action. Phosphorus is essential for growth and maintenance of the skeleton and for generating high energy phosphate compounds.…”

“…The renal proximal tubule is the primary site of phosphate homeostasis and hormone-dependent phosphate transport. The NPT2A sodium-dependent phosphate cotransporter (SLC34A1) in proximal tubules is regulated by PTH and FGF23 (1,2). PTH and FGF23 reduce phosphate uptake by sequestering and down-regulating NPT2A, thereby enhancing urinary phosphate excretion (3,4).…”

The Molecular Basis of Calcium and Phosphorus Inherited Metabolic Disorders

“…The recommended Ca intake for infants is 200 mg/24 h which gradually increases in childhood, while the highest requirements are noted during adolescence and individuals over 50 years old [ 2 ]. About 40% of dietary Ca is absorbed from the gastrointestinal tract via a paracellular pathway and an active transcellular pathway both potentially regulated by 1,25(OH) 2 D 3 [ 3 , 4 , 5 ]. Half of the absorbed Ca leaves the body in urine and feces.…”