PSEUDOHYPOPARATHYROIDISM FROM MATERNAL BUT NOT PATERNAL TRANSMISSION OF A Gαs FRAMESHIFT MUTATION. • 552

Abstract

The G-protein subunit Gαs couples many hormone receptors, including those for parathyroid hormone (PTH) and thyrotropin (TSH), to the stimulation of adenylyl cyclase within cells. We and others have demonstrated the consistent association of mutations leading to decreased function of Gαs with Albright hereditary osteodystrophy (AHO), characterized by rounded facies, short stature, and brachymetacarpia. Less consistent has been the relationship of these Gαs mutations with the PTH and TSH resistance seen in pseudohypoparathyroidism type Ia (PHP-Ia). In clinical studies of pedigrees affected by AHO, there is a strong association of maternal transmission of the AHO phenotype with the full expression of PHP-Ia in the offspring of these mothers. We studied in more detail a pedigree affected by AHO and PHP-Ia for which we previously reported finding a 4-bp deletion in one allele of the gene for Gαs. Specific exons of the Gαs gene were amplified by PCR with GC-tailed oligonucleotides, using as a template DNA from leukocytes of family members spanning three generations. Denaturing gradient gel electrophoresis of PCR-amplified exon 7 fragments showed that the patriarch of this pedigree, who was affected by mild short stature but no clinical hormonal abnormalities, carried the same heterozygous pattern previously shown by dideoxynucleotide sequencing to represent a deletion of 4 nucleotides in exon 7 resulting in a reading frame shift. Of his three offspring (1 male, 2 female) who inherited the same mutation, erythrocyte Gαs activity as measured by an S49cyc- complementation assay ranged from 58% ± 7.1 to 85% ± 8.5 that of normal control subjects, with all affected by AHO but without any hormonal abnormalities of PHP-Ia. Offspring of the two women with AHO had Gαs activity from 52% ± 12 to 55% that of controls, and all had AHO + hormonal abnormalities (PTH & TSH elevation, hypocalcemia, hyperphosphatemia) consistent with PHP-Ia. In conclusion, this family showed autosomal dominant co-inheritance of AHO and a Gαs frameshift mutation, with expression of hormone resistance (PHP-Ia) associated with maternal but not paternal transmission.