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.