HSH is caused by decreased intestinal magnesium reabsorption through TRPM6 channels. When expressed in cells, TRPM6 produces outwardly rectifying currents with the outward portion composed of Na+ ions and the inward portion of divalent cations (particularly magnesium and calcium). Inward flow of sodium ions is blocked by extracellular divalent cations. Increased intracellular magnesium concentrations also decrease current through TRPM6 channels. There are currently more than 30 known mutations in TRPM6 that are associated with HSH and these mutations are spreading throughout the gene (table 1). Of the eight HSH mutations that have been tested, none have shown to produce whole-cell current. The S141L mutation, one of the few missense mutations, has been of particular interest to researchers. They have found that it prevents coassembly with TRPM7 (and presumably other TRPM6 subunits) and lacks the ability to traffic to the membrane. Whether other mutants are able to traffic properly to the surface or coassemble has not yet been further studied. While the<unk>  in patients with HSH is a direct result of TRPM6 mutations,<unk>  is an indirect,<unk>  result. Parathyroid gland secretion of PTH can be altered by changes in serum magnesium levels. The decreased serum magnesium levels seen in HSH result in decreased PTH secretion. PTH, in turn, controls the availability of serum calcium. Decreasing PTH levels cause a decrease in calcium availability in serum and, thus, the neurological symptoms of HSH. +Table 1. TRPM6 mutations associated with<unk>  Mutation Location Functional? Reference Nucleotide Amino acid c.C166T R56X N-terminus c.C422T S141L N-terminus No ,,, c.G469T E157X N-terminus c.T521G I174R N-terminus c.668delA D223fsX263 N-terminus c.1010+5G→C Splicing N-terminus c.A1060C T354P N-terminus c.1134+5G→A Splicing N-terminus c.1208-1G→A Splicing N-terminus c.1280delA H427fsX429 N-terminus No , c.1308+1G→A Splicing N-terminus c.C1437A Y479X N-terminus c.C1450T R484X N-terminus c.C1769G S590X N-terminus No ,, c.del1796-1797 P599fsX609 N-terminus c.2009+1G→A Splicing N-terminus , c.G2120A C707Y N-terminus c.2207delG R736fsX737 N-terminus No ,, c.2537-2A→T Splicing N-terminus c.2667+1G→A Splicing , c.C2782T R928X M3 No c.del Ex 21 M4 c.Del2831-2832insG I944fsX959 M4-M5 c.3209-68A→G Splicing c.del Ex 22 + 23 M5-6 C.3537-1G→A Splicing , c.3779-91del Q1260fsX1283 C-terminus , c.del Ex 25 - 27 C-terminus c.del Ex 26 Y1533X C-terminus No c.5017-18delT L1673fsX1675 C-terminus No c.del Ex 31 + 32 C-terminus No c.5057+2T→C Splicing C-terminus c.A5775G Splicing C-terminus
Hypomagnesemia with secondary hypocalcemia
Exercise-associated hyponatremia
Chronic recurrent multifocal osteomyelitis
Hypotonic hyponatremia
Normophosphatemic familial tumoral calcinosis
Secondary hyperparathyroidism
Familial hypocalciuric hypercalcemia
Isotonic hyponatremia