Dn. Finegold et al., PRELIMINARY LOCALIZATION OF A GENE FOR AUTOSOMAL-DOMINANT HYPOPARATHYROIDISM TO CHROMOSOME 3Q13, Pediatric research, 36(3), 1994, pp. 414-417
A large family in which hypoparathyroidism was observed to segregate a
s an autosomal dominant trait in three generations was identified. Mut
ation in the PTH gene was excluded by linkage and single-stranded conf
ormational analysis. The hypocalcemic phenotype in this family was map
ped by linkage analysis using short, tandem-repeat polymorphisms to th
e region of chromosome 3q13. A maximum led score of 2.71 at Theta = 0.
0 was observed with marker D3S1303. Positive lod scores were observed
at Theta = 0.0 with markers flanking D3S1303. Multipoint linkage analy
sis gave a lod score of 2.71 for the region flanking D3S1303. Simulati
on using the computer program SLINK showed that a led score of 2.71 at
Theta = 0.0 was the maximum lod score possible given the pedigree str
ucture. The simulation also showed that given the structure of the ped
igree the probability of observing a lod score of 2.71 at Theta = 0.0
by chance was 1 in 1000. The data presented above provide important pr
eliminary evidence supporting linkage to chromosome 3q13. This region
contains a Ca2+-sensing receptor gene that is proposed as a key signal
transduction element for changes in extracellular Ca2+ concentrations
in mechanisms of regulation of PTH secretion from parathyroid cells.
The mutation in this family may activate the Ca2+-sensing receptor sup
pressing PTH secretion and lowering the ''set point'' for serum calciu
m levels.