Genetic background of HSH in three Polish families and a patient with an X;9 translocation

Abstract

Hypomagnesemia with secondary hypocalcemia (HSH) is a rare inherited disease, characterised by neurological symptoms, such as tetany, muscle spasms and seizures, due to hypocalcemia. It has been suggested that HSH is genetically heterogeneous, but only one causative gene, TRPM6, on chromosome 9 has so far been isolated. We have now studied the genetic background of HSH in four Polish patients belonging to three families, and a HSH patient carrying an apparently balanced X;9 translocation. The translocation patient has long been considered as an example of the X-linked form of HSH. We identified six TRPM6 gene mutations, of which five were novel, in the Polish patients. All the alterations were either nonsense/splicing or missense mutations. The clinical picture of the patients was similar to the HSH patients reported earlier. No genotype -phenotype correlation could be detected. Sequencing did not reveal any TRPM6 or TRPM7 gene mutations in the female HSH patient with an X;9 translocation. Isolation of the translocation breakpoint showed that the chromosome 9 specific breakpoint mapped within satellite III repeat sequence. The X-chromosomal breakpoint was localised to the first intron of the vascular endothelial growth factor gene, VEGFD. No other sequence alterations were observed within the VEGFD gene. Even though the VEGFD gene was interrupted by the X;9 translocation, it seems unlikely that VEGFD is causing the translocation patient's HSH-like phenotype. Furthermore, re-evaluation of patient's clinical symptoms suggests that she did not have a typical HSH.

New TRPM6 missense mutations linked to hypomagnesemia with secondary hypocalcemia

“…These include stop mutations, splice-site mutations, frame-shift mutations, and deletions. 10,[14][15][16][17]20,31 Furthermore, five missense mutations leading to HSH have been described so far, from which only S 141 L and P 1017 R were further studied at the molecular level. 10,19 The S 141 L mutation found in the highly conserved serine 141 resulted in impaired trafficking of TRPM6 to the membrane, 10,18 while the P 1017 R mutation located in the putative pore-forming region is the only known example of a mutation affecting TRPM6-gating properties without altering assembly or trafficking events.…”

“…19 The remaining three-point mutations were found in three Polish families; however, the authors did not report whether HSH was a consequence of either TRPM6 trafficking or functional impairment. 20 Overall, 34 different mutations have been previously described, from which only five are point mutations, thus B85% of mutations are truncating. This study contributes five previously unknown missense mutations in the TRPM6 gene leading to HSH.…”

“…18,19 Another three-point mutations leading to HSH, where the underlying molecular mechanism was not disclosed, have also been published. 20 Here, we characterize a new set of five missense mutations identified in five HSH patients. The functional consequence of these novel mutations was studied in mammalian Human embryonic kidney (HEK) 293 cells by electrophysiological and biochemical analyses.…”

Renal TRPathies

“…In contrast to these studies, other studies 11,77,96 provided biophysical, biochemical, and cellular evidence that TRPM6 displays features remarkably different from those of TRPM7. In particular, TRPM6 expressed in HEK293 cells, Xenopus oocytes, or DT40 lymphocytes 96,97 does not efficiently form homomultimeric channel complexes in the plasma membrane and required TRPM7 for co-targeting to the cell surface.…”

“…11,76 Functional consequences of the naturally occurring TRPM6 mutations include introduction of frame shifts, stop codons, or disruption of exon splice sites. 66,77,78 Only five missense mutations have been identified so far (Figure 2A) 66,77,78 ; their impact on TRPM6 function is discussed next.…”