Molecular Definition of Pseudohypoparathyroidism Variants

Abstract

Pseudohypoparathyroidism (PHP) and pseudopseudohypoparathyroidism (PPHP) are caused by mutations and/or epigenetic changes at the complex GNAS locus on chromosome 20q13.3 that undergoes parent-specific methylation changes at several differentially methylated regions (DMRs). GNAS encodes the alpha-subunit of the stimulatory G protein (Gsα) and several splice variants thereof. PHP type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal exons 1-13. Heterozygosity of these maternal GNAS mutations cause PTH-resistant hypocalcemia and hyperphosphatemia because paternal Gsα expression is suppressed in certain organs thus leading to little or no Gsα protein in the proximal renal tubules and other tissues. Besides biochemical abnormalities, PHP1A patients show developmental abnormalities, referred to as Albright’s Hereditary Osteodystrophy (AHO). Some, but not all of these AHO features are encountered also in patients affected by PPHP, who carry paternal Gsα-specific mutations and typically show no laboratory abnormalities. The autosomal dominant PHP type Ib (AD-PHP1B) is caused by heterozygous maternal deletions within GNAS or STX16, which are associated with loss-of-methylation (LOM) at the A/B DMR alone or at all maternally methylated GNAS exons. LOM of exon A/B and the resulting biallelic expression of A/B transcript reduces Gsα expression thus leading to hormonal resistance. Epigenetic changes at all differentially methylated GNAS regions are also observed in sporadic PHP1B, which is the most frequent PHP1B variant. However, this disease variant remains unresolved at the molecular level, except for rare cases with paternal uniparental isodisomy or heterodisomy of chromosome 20q (patUPD20q).

Functional Properties of Two Distinct PTH1R Mutants Associated With Either Skeletal Defects or Pseudohypoparathyroidism

“…1 B , C , Table 1 ). On the PTH1R‐R186H mutant, the maximum response to PTH( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ) was moderately higher than that observed on PTH1R‐WT (Emax = 118% ± 4%, p = 0.002, Table 1 ), whereas the potency of the response tended to be slightly (approximately threefold) weaker than that of the ligand on PTH1R‐WT. The reason for the increase in Emax is not clear, because the patient phenotype predicts a deficiency in responsiveness to PTH, which is at least suggested by the trend toward reduced potency.…”

“…5 C , Table 2 ). The relative responses induced by PTH(1‐28) and PTHrP( 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ) on PTH1R‐R186H therefore differed from those obtained on this mutant receptor with the intact peptides, as the Emax of the response to PTH(1‐34) was increased by ~18% and potency tended to be approximately threefold weaker, whereas the response to PTHrP(1‐36) was unchanged for efficacy and approximately twofold stronger in potency. These differences suggest that residues in the 29–34 and 29–36 regions of PTH(1‐34) and PTHrP(1‐36), respectively, can modulate the impact that the R186H mutation located in TM1 of the receptor has on the overall ligand interaction process.…”

“…The phenotypes suggest a condition similar to pseudohypoparathyroidism type 1b (PHP1B), which is typically linked to epigenetic mutations in the guanine nucleotide binding protein, alpha stimulating (GNAS) locus, which encodes the stimulatory G protein, Gαs. ( 20 ) Genetic analysis of the index case, however, revealed the homozygous PTH1R missense mutation that changes arginine‐186 in the protein to a histidine (R186H). ( 19 ) Two siblings of the index case also carry the same homozygous PTH1R mutation, and both presented with elevated levels of PTH, low serum levels of calcium, intracranial calcifications, and no obvious skeletal or developmental abnormality.…”

A Distinct Variant of Pseudohypoparathyroidism (PHP) First Characterized Some 41 Years Ago Is Caused by the 3‐kbSTX16 Deletion

“…(22‐ 24 ) A 3‐kb deletion was subsequently identified within STX16 , the gene encoding syntaxin 16, which is now known to be the most frequent molecular cause of AD‐PHP1B. ( 12,25,26 )…”

“…Instead, genetic linkage studies revealed that the autosomal dominant variant of PHP1B (AD-PHP1B) is an imprinted disorder that is caused by a maternally inherited mutation centromeric of GNAS (20,21), which is furthermore associated with epigenetic changes at this locus (22). A 3kb deletion was subsequently identified within STX16, the gene encoding syntaxin 16, which is now known to be the most frequent molecular cause of AD-PHP1B (23)(24)(25).…”