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) was studied in three inbred Bedouin kindreds from Israel, The three k indreds, one extended and two nuclear families, contained 13 affected individuals, 11 males and two females, Assuming that the individuals a ffected with hypomagnesemia shared a chromosomal region inherited from a common ancestor, we used a DNA pooling strategy in a genome-wide se arch for loci which show homozygosity for shared alleles in affected i ndividuals, DNA samples from affected individuals within a single kind red were pooled and used as the template for PCR amplification of shor t tandem repeat polymorphic markers (STRPs), Pealed DNA from unaffecte d siblings and parents were used as controls, A shift towards homozygo sity was observed in the affected DNA pool compared with the control p ools with D9S301 (GATA7D12), Genotyping of individual DNA samples with D9S301 and several flanking markers confirmed linkage to chromosome 9 with maximum LOD scores of 3.4 (theta = 0.05), 3.7 (theta = 0) and 2. 3 (theta = 0) for the three families, We have identified a 14 cM inter val on chromosome 9 (9q12-9q22.2), flanked by proximal marker D9S1874 and distal marker D9S1807, within which all affected individuals from the three kindreds are homozygous for a shared haplotype, The disease segregates with a common affected haplotype in the three families, sug gesting that hypomagnesemia is caused by a common ancestral mutation i n these families, Although HSH has been previously reported to be X li nked, these linkage data demonstrate that the disorder is an autosomal recessive disease in these kindreds, Mapping of a chromosomal breakpo int in a somatic cell line established from a patient with HSH and a b alanced X; 9 translocation placed the chromosomal breakpoint in a 500 kb region flanked by D9S1844 and D9S273, Identification of the gene re sponsible for hypomagnesemia will provide insight into the regulation of this essential cation.