Familial hypomagnesemia maps to chromosome 9q, not to the X chromosome: genetic linkage mapping and analysis of a balanced translocation breakpoint

Familial hypomagnesemia with secondary hypocalcemia (HSH) (MIM 307600) wasstudied in three inbred Bedouin kindreds from Israel. The three kindreds,one extended and two nuclear families, contained 13 affected individuals,11 males and two females. Assuming that the individuals affected withhypomagnesemia shared a chromosomal region inherited from a commonancestor, we used a DNA pooling strategy in a genome-wide search for lociwhich show homozygosity for shared alleles in affected individuals. DNAsamples from affected individuals within a single kindred were pooled andused as the template for PCR amplification of short tandem repeatpolymorphic markers (STRPs). Pooled DNA from unaffected siblings andparents were used as controls. A shift towards homozygosity was observed inthe affected DNA pool compared with the control pools with D9S301(GATA7D12). Genotyping of individual DNA samples with D9S301 and severalflanking markers confirmed linkage to chromosome 9 with maximum LOD scoresof 3.4 (theta = 0.05), 3.7 (theta = 0) and 2.3 (theta = 0) for the threefamilies. We have identified a 14 cM interval on chromosome 9(9q12-9q22.2), flanked by proximal marker D9S1874 and distal markerD9S1807, within which all affected individuals from the three kindreds arehomozygous for a shared haplotype. The disease segregates with a commonaffected haplotype in the three families, suggesting that hypomagnesemia iscaused by a common ancestral mutation in these families. Although HSH hasbeen previously reported to be X linked, these linkage data demonstratethat the disorder is an autosomal recessive disease in these kindreds.Mapping of a chromosomal breakpoint in a somatic cell line established froma patient with HSH and a balanced X;9 translocation placed the chromosomalbreakpoint in a 500 kb region flanked by D9S1844 and D9S273. Identificationof the gene responsible for hypomagnesemia will provide insight into theregulation of this essential cation.