BACKGROUND: Primary hypomagnesemia with secondary hypocalcemia (HSH) is a rare genetic disorder. Dysfunctional transient receptor potential melastatin 6 causes impaired intestinal absorption of magnesium, leading to low serum levels accompanied by hypocalcemia. Typical signs at initial manifestation are generalized seizures, tetany, and/or muscle spasms. CASE REPORT: We present a 5 w/o female manifesting tonic-clonic seizures. Laboratory tests detected severe hypomagnesemia and hypocalcemia. The molecular genetic analysis revealed two novel mutations within the TRPM6 gene c.3308dupC (p.Pro1104Thrfs*28) (p.P1104Tfs*28) and c.3958C>T (p.Gln1302*) (p.Q1302*) and the patient was successfully treated with Mg supplementation. CONCLUSION: Ion disbalance should be taken into account in the differential diagnosis of infantile seizures. Accurate diagnosis of HSH together with appropriate treatment are crucial to prevent irreversible neurological outcomes.

• Klíčová slova
• hypocalcemia, hypomagnesemia, infantile seizures, transient receptor potential melastatin 6,
• MeSH
• hořčík MeSH
• hyperkalciurie MeSH
• hypokalcemie * genetika   MeSH
• kationtové kanály TRPM * genetika   MeSH
• lidé MeSH
• mutace MeSH
• nedostatek hořčíku * vrozené   genetika   MeSH
• nefrokalcinóza MeSH
• vrozené poruchy tubulárního transportu MeSH
• záchvaty genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• hořčík MeSH
• kationtové kanály TRPM * MeSH
• TRPM6 protein, human MeSH Prohlížeč

Transient receptor potential (TRPs) channels are crucial downstream targets of calcium signalling cascades. They can be modulated either by calcium itself and/or by calcium-binding proteins (CBPs). Intracellular messengers usually interact with binding domains present at the most variable TRP regions-N- and C-cytoplasmic termini. Calmodulin (CaM) is a calcium-dependent cytosolic protein serving as a modulator of most transmembrane receptors. Although CaM-binding domains are widespread within intracellular parts of TRPs, no such binding domain has been characterised at the TRP melastatin member-the transient receptor potential melastatin 6 (TRPM6) channel. Another CBP, the S100 calcium-binding protein A1 (S100A1), is also known for its modulatory activities towards receptors. S100A1 commonly shares a CaM-binding domain. Here, we present the first identified CaM and S100A1 binding sites at the N-terminal of TRPM6. We have confirmed the L520-R535 N-terminal TRPM6 domain as a shared binding site for CaM and S100A1 using biophysical and molecular modelling methods. A specific domain of basic amino acid residues (R526/R531/K532/R535) present at this TRPM6 domain has been identified as crucial to maintain non-covalent interactions with the ligands. Our data unambiguously confirm that CaM and S100A1 share the same binding domain at the TRPM6 N-terminus although the ligand-binding mechanism is different.

• Klíčová slova
• CaM and S100A1, TRPM6, binding domain, calmodulin binding motif, fluorescence anisotropy, molecular modelling,
• MeSH
• kalmodulin chemie   MeSH
• kationtové kanály TRPM chemie   MeSH
• lidé MeSH
• molekulární modely * MeSH
• proteinové domény MeSH
• proteiny S100 chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kalmodulin MeSH
• kationtové kanály TRPM MeSH
• proteiny S100 MeSH
• S100A1 protein MeSH Prohlížeč
• TRPM6 protein, human MeSH Prohlížeč

Melastatin transient receptor potential (TRPM) channels belong to one of the most significant subgroups of the transient receptor potential (TRP) channel family. Here, we studied the TRPM5 member, the receptor exposed to calcium-mediated activation, resulting in taste transduction. It is known that most TRP channels are highly modulated through interactions with extracellular and intracellular agents. The binding sites for these ligands are usually located at the intracellular N- and C-termini of the TRP channels, and they can demonstrate the character of an intrinsically disordered protein (IDP), which allows such a region to bind various types of molecules. We explored the N-termini of TRPM5 and found the intracellular regions for calcium-binding proteins (CBPs) the calmodulin (CaM) and calcium-binding protein S1 (S100A1) by in vitro binding assays. Furthermore, molecular docking and molecular dynamics simulations (MDs) of the discovered complexes confirmed their known common binding interface patterns and the uniqueness of the basic residues present in the TRPM binding regions for CaM/S100A1.

• MeSH
• kalmodulin * chemie   MeSH
• kationtové kanály TRPM * chemie   metabolismus   MeSH
• proteiny S100 metabolismus   MeSH
• simulace molekulového dockingu MeSH
• vápník metabolismus   MeSH
• vazebná místa MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kalmodulin * MeSH
• kationtové kanály TRPM * MeSH
• proteiny S100 MeSH
• vápník MeSH