Alternative titles; symbols
SNOMEDCT: 717792007; ORPHA: 79444; DO: 0051013;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20q13.32 | Pseudohypoparathyroidism Ic | 612462 | Autosomal dominant | 3 | GNAS | 139320 |
A number sign (#) is used with this entry because a subset of patients with a diagnosis of pseudohypoparathyroidism type Ic (PHP1C) have been found to carry a heterozygous mutation on the maternal allele of the GNAS gene (139320) on chromosome 20q13.
Because the phenotype of PHP Ic is essentially identical to that of PHP Ia (103580), except for retained erythrocyte Gs activity in PHP Ic which may result from the location of the mutation within the GNAS gene, it is unclear whether PHP Ic represents a subgroup of PHP Ia or whether it constitutes a distinct entity (Bastepe, 2008).
For a general description, classification, and discussion of the genetics of pseudohypoparathyroidism (PHP), see PHP1A (103580).
Pseudohypoparathyroidism type Ic (PHP1C) is characterized by resistance to parathyroid hormone (PTH; 168450) as well as to other hormones. It is associated with a constellation of physical features referred to as Albright hereditary osteodystrophy (AHO), which includes short stature, obesity, round facies, subcutaneous ossifications, brachydactyly, and other skeletal anomalies. Some patients have mental retardation. Laboratory studies in patients with PHP Ic show a decreased cellular cyclic AMP (cAMP) response to infused PTH, but no defect in activity of the erythrocyte Gs protein (Mantovani and Spada, 2006).
Farfel et al. (1981) reported a family in which several affected individuals had classic PHP type I, including PTH-resistance, hypothyroidism, and skeletal abnormalities such as short stature and brachydactyly. There was a decreased urinary cAMP response to PTH, but normal erythrocyte activity of N-protein, a receptor-cyclase coupling component. Farfel et al. (1981) postulated a defect distal to the PTH receptor in these families.
Linglart et al. (2002) reported a girl with pseudohypoparathyroidism, multiple hormonal resistance, and AHO, but normal erythrocyte Gs activity. The phenotype was referred to as PHP type Ic.
Thiele et al. (2011) reported 5 patients from 4 unrelated families with a diagnosis of PHP Ic. Two patients were dizygotic twins. All had round face and brachymetacarpia, 3 were obese, and 2 had short stature. One had mental retardation. All had significantly increased serum PTH, all but 1 had decreased serum calcium, and all had increased TSH, suggesting end-organ hormone resistance. Erythrocyte Gs-alpha activity was normal in cellular studies. All mothers of the patients had milder features, including short stature, round face, or brachymetacarpia, but none had evidence of hormonal resistance; 2 were given a diagnosis of pseudopseudohypoparathyroidism (PPHP; 612463).
In a patient with a phenotype consistent with PHP Ic, Linglart et al. (2002) identified a heterozygous nonsense mutation in the GNAS gene (Y391X; 139320.0035) that terminated the protein only 4 amino acids before the wildtype stop codon. The findings indicated that the mutation did not affect adenylate cyclase activity, but interfered somehow with receptor-mediated activation. Linglart et al. (2002) noted that the C terminus is required for receptor coupling, and postulated that the Y391X mutation in this patient interrupted receptor coupling, leading to hormone resistance. The findings showed the limits of the erythrocyte Gs bioassay used in the study, which was not dependent on receptor-mediated activation.
Despite the molecular findings of Linglart et al. (2002), Bastepe (2008) stated that it was unclear whether patients with so-called PHP Ic represent a subgroup of PHP Ia patients with GNAS mutations that affect receptor coupling or whether they constitute a distinct group in whom the genetic defect lies downstream of receptor-activated cAMP generation.
In 5 patients from 4 unrelated families with a diagnosis of PHP Ic, Thiele et al. (2011) identified 3 different heterozygous mutations in the GNAS gene (139320.0038; 139320.0039; 139320.0040), all of which were inherited from a mother with mild skeletal features but no end-organ hormonal resistance. All mutations occurred in exon 13, in the alpha-5-helix in the C terminus. In vitro functional expression studies showed that all the mutant proteins caused an absence or decrease of receptor-mediated cAMP production, with normal receptor-independent cAMP production. The findings indicated normal Gs-alpha activity, but a selective defect in Gs-alpha-receptor coupling functions. GNAS mutations were not found in 27 additional patients with a diagnosis of PHP Ic. Thiele et al. (2011) concluded that these patients represented a new subgroup of PHP.
Bastepe, M. The GNAS locus and pseudohypoparathyroidism. Adv. Exp. Med. Biol. 626: 27-40, 2008. [PubMed: 18372789] [Full Text: https://doi.org/10.1007/978-0-387-77576-0_3]
Farfel, Z., Brothers, V. M., Brickman, A. S., Conte, F., Neer, R., Bourne, H. R. Pseudohypoparathyroidism: inheritance of deficient receptor-cyclase coupling activity. Proc. Nat. Acad. Sci. 78: 3098-3102, 1981. [PubMed: 6265935] [Full Text: https://doi.org/10.1073/pnas.78.5.3098]
Linglart, A., Carel, J. C., Garabedian, M., Le, T., Mallet, E., Kottler, M. L. GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance. J. Clin. Endocr. Metab. 87: 189-197, 2002. [PubMed: 11788646] [Full Text: https://doi.org/10.1210/jcem.87.1.8133]
Mantovani, G., Spada, A. Mutations in the Gs alpha gene causing hormone resistance. Best Pract. Res. Clin. Endocr. Metab. 20: 501-513, 2006. [PubMed: 17161328] [Full Text: https://doi.org/10.1016/j.beem.2006.09.001]
Thiele, S., de Sanctis, L., Werner, R., Grotzinger, J., Aydin, C., Juppner, H., Bastepe, M., Hiort, O. Functional characterization of GNAS mutations found in patients with pseudohypoparathyroidism type Ic defines a new subgroup of pseudohypoparathyroidism affecting selectively Gs-alpha-receptor interaction. Hum. Mutat. 32: 653-660, 2011. [PubMed: 21488135] [Full Text: https://doi.org/10.1002/humu.21489]