In a patient with PHP1A (103580), Weinstein et al. (1992) identified a heterozygous 4-bp deletion (565delCTGA) in exon 7 of the GNAS1 gene, resulting in a frameshift and premature stop codon. Analysis of lymphocyte RNA by reverse transcription-PCR and direct sequencing showed that the GNAS1 allele bearing the mutation was not expressed as mRNA. Consistent with this, Northern blot analysis revealed an approximately 50% deficiency in steady-state levels of GNAS1 mRNA.
Ahmed et al. (1998) identified this deletion mutation in 2 unrelated families with PHP Ia.
Shore et al. (2002) provided direct evidence that the 4-bp deletion can cause either progressive osseous heteroplasia (POH; 166350) or Albright hereditary osteodystrophy without hormone resistance (PPHP; 612463) in the same family. Five sisters with POH had inherited this mutation from the father in whom the mutation was nonpenetrant. Three offspring of these sisters had AHO, including traces of subcutaneous ossification. Shore et al. (2002) suggested that POH requires paternal inheritance of a GNAS1 mutation, whereas hormone resistance is more likely to occur when the genetic defect is maternally inherited.
Ahmed et al. (2002) cautioned against a premature conclusion that POH may require paternal inheritance. In a family reported by Ahmed et al. (1998), the 4-bp deletion was found in a brother and sister and in their mother but not in their father. Aside from brachymetacarpia and short stature, the mother did not have features of AHO. The daughter had typical features of AHO and hormone resistant PHP1A; in contrast, her brother presented in the first year of life with ossification of subcutaneous tissue that was followed by progressive, generalized heterotopic ossification of skeletal muscle, without any clear evidence of hormone resistance. These cases exemplified the wide phenotypic heterogeneity in persons with mutations in GNAS1, even within 1 family.
Bastepe and Juppner (2002) suggested that, like some patients who have either PHP type Ia or PHP type Ib, the son described by Ahmed et al. (1998) may have developed resistance to parathyroid hormone later in life or not at all. Given that the patient's sister and mother had PHP type Ia and PPHP, respectively, POH resulting from maternally inherited GNAS1 mutations may actually represent an incomplete form of PHP type Ia. Bastepe and Juppner (2002) suggested that the underlying mechanism for this form of POH may be distinct from that described by Shore et al. (2002), which appears to result only from paternally inherited GNAS1 mutations.
Adegbite et al. (2008) identified heterozygosity for the 565delCTGA mutation in the GNAS gene in 13 POH cases (10 familial cases among 3 different families, and 3 individual spontaneous cases). The mutation resulted in variable severity and pleiotropy, both in family members and in unrelated sporadic cases.
