ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000020.10) (NC_000020.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
9876352 Ahmed et al. (1998) describe two unrelated families with a 4 bp deletion in exon 7 that is associated with a frameshift at codons 189 and 190 and a termination at codon 202. This is predicted to result in a truncated Gs? protein that lacks the GTP binding and G-protein coupled receptor interaction domains. Each family included individuals with both the PHP1a and PPHP phenotypes. Two other families with other missense mutations are also reported.
11095461 Mantovani et al. (2000) describe two novel frameshift mutations in GNAS: The first is a heterozygous 2-bp deletion within codon 287 in exon 11, which results in a premature stop codon in position 298. The same deletion was found in the patient's mother; both were affected with PHP1a. The other novel mutation was a heterozygous 1-bp deletion within exon 1 (codon 38), which results in a premature stop codon in position 57 (Fig. 2?). This mutation was found in a patient affected with PPH Ia, as well as the patient's mother (who was affected with PPHP). No mutation was detected in the unaffected father and brother. This paper also describes two previously reported frameshift mutations, including the one described in Ahmed et al. (1998).
11600516 Ahrens et al. (2001) identified 4 additional novel frameshift mutations amongst families with PHP1a and PPHP phenotypes.

Haploinsufficiency phenotype comments:

Loss of function mutations in GNAS have been associated with pseudohypoparathyroidism Ia (PHP1A), pseudopseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH). From (#103580): "Pseudohypoparathyroidism [PHP] is a term applied to a heterogeneous group of disorders whose common feature is end-organ resistance to parathyroid hormone (PTH; 168450). In addition to PTH resistance, PHP Ia is characterized by resistance to other hormones, including thyroid-stimulating hormone (TSH; see TSHB, 188540) and gonadotrophins. PHP Ia is associated with a constellation of clinical 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 (Mantovani and Spada, 2006). In contrast, pseudopseudohypoparathyroidism (PPHP; 612463) is characterized by the physical findings of AHO but without hormone resistance (Kinard et al., 1979; Fitch, 1982; Mantovani and Spada, 2006). PHP1A occurs only after maternal inheritance of the molecular defect, whereas PPHP occurs only after paternal inheritance of the molecular defect (Davies and Hughes, 1993; Wilson et al., 1994). This is an example of imprinting, with differential gene expression depending on the parent of origin of the allele." From (#166350): "Progressive osseous heteroplasia (POH) is a rare autosomal dominant disorder characterized by dermal ossification beginning in infancy, followed by increasing and extensive bone formation in deep muscle and fascia (Kaplan et al., 1994). The molecular defect causing POH is the same as that causing PPHP: an inactivating GNAS mutation caused only by paternal inheritance of the mutant allele. However, patients with PPHP have a constellation of physical findings referred to as Albright hereditary osteodystrophy (AHO; see 103580) that is often not seen in patients with POH. Bastepe and Juppner (2005) suggested that POH may be an extreme end of the spectrum of the AHO features seen in PPHP." Also of note, from (#603233): "Pseudohypoparathyroidism type Ib (PHP Ib) is caused by deletions in the differentially methylated region (DMR) of the GNAS (139320) locus. One deletion (139320.0031) removes the entire NESP55 DMR and exons 3 and 4 of the antisense transcript of the GNAS gene (GNASAS; 610540.0001). PHP1B can also result from deletion in the STX gene (603666), a long-range control element of methylation at the GNAS locus. These methylation and imprinting defects result in the absence of expression of the maternal Gs-alpha isoform."

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Of note, from (#139320): "Activating gain-of-function mutations in the GNAS1 gene result in the McCune-Albright syndrome (MAS; 174800), polyostotic fibrous dysplasia (POFD; see 174800), and various endocrine tumors. These activating mutations are present in the mosaic state, resulting from a postzygotic somatic mutation appearing early in the course of development which yields a monoclonal population of mutated cells within variously affected tissues. The nonmosaic state for activating mutations is presumably lethal to the embryo (Aldred and Trembath, 2000; Lumbroso et al., 2004)." No whole-gene duplications of GNAS have been reported at this time.