GNAS1Lesions in Pseudohypoparathyroidism Ia and Ic: Genotype Phenotype Relationship and Evidence of the Maternal Transmission of the Hormonal Resistance

Abstract

We conducted clinical and biological studies including screening for mutations in the gene encoding the alpha subunit of G(s) (GNAS1) in 30 subjects (21 unrelated families) with Albright's hereditary osteodystrophy (AHO), pseudohypoparathyroidism (PHP); and decreased erythrocyte G(s) activity (PHP-Ia; n = 19); AHO and decreased erythrocyte G(s) activity (isolated AHO; n = 10); or AHO, hormonal resistance, and normal erythrocyte G(s) activity (PHP-Ic; n = 1). A heterozygous GNAS1 gene lesion was found in 14 of 17 PHP-Ia index cases (82%), including 11 new mutations and a mutational hot-spot involving codons 189-190 (21%). These lesions lead to a truncated protein in all but three cases with missense mutations R280K, V159M, and D156N. In the patient diagnosed with PHP-Ic, G(s)alpha protein was shortened by just four amino acids, a finding consistent with the conservation of G(s) activity in erythrocytes and the loss of receptor contact. No GNAS1 lesions were found in individuals with isolated AHO that were not relatives to PHP-Ia patients (n = 5). Intrafamilial segregation analyses of the mutated GNAS1 allele in nine PHP-Ia patients established that the mutation had either occurred de novo on the maternal allele (n = 4) or had been transmitted by a mother with a mild phenotype (n = 5). This finding is consistent with an imprinting of GNAS1 playing a role in the clinical phenotype of loss of function mutations and with a functional maternal GNAS1 allele having a predominant role in preventing the hormonal resistance of PHP-Ia.

A patient with features of albright hereditory osteodystrophy and unusual neuropsychiatric findings without coding Gsalpha mutations

“…Sussane Thiele et al described 5 patients diagnosed as PHP-Ic in whom they found TSH and PTH resistance, with normal Gsα activity and inherited maternal inactivating mutations in GNAS exons [21]. Linglart et al [22] in a study on genotype, phenotype relationship on the maternal transmission of the hormonal resistance did not observe any relationship between the erythrocyte Gsα activity and the phenotype which may justify our findings in this patient.…”

From pseudohypoparathyroidism to inactivating PTH/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network

“…Calcitonin resistance has been described without clinical features in patients affected with PHP1A (27). Elevated follicular-stimulating hormone (FSH) and luteinizing hormone (LH) levels were reported both by us and Namnoum et al (78,100). Glucagon and adrenaline resistances were demonstrated in patients Figure 3 Patterns of brachydactyly type E associated with iPPSD.…”

“…Different molecular defects have been identified in patients with PHP1C, i.e. LOI at GNAS and four lossof-function mutations in the GNAS carboxyl-terminus leading to a conserved adenylyl cyclase receptorindependent activation but disrupted receptormediated activation (29,30,78).…”

Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo

“…Consistent with this imprinted mode of inheritance of hormone resistance, Gs␣ expression occurs predominantly from the maternal allele in certain human tissues, including the thyroid gland (9)(10)(11), the ovary (9), and the pituitary gland (12). In the renal cortex, there is evidence for both biallelic (13) and maternal expression of Gs␣ (14). AHO, unlike hormone resistance, develops after both paternal and maternal transmission of Gs␣ mutations.…”