Progressive osseous heteroplasia (POH, MIM 166350) is a rare autosomal dominant disorder characterised by extensive dermal ossification during childhood, followed by widespread heterotopic ossification of skeletal muscle and deep connective tissue. Recently, genetic basis was found to be common with Albrights hereditary osteodystrophy (AHO) (Shore et al., 2002): paternally inherited inactivating mutations of the GNAS1 gene were found. GNAS1 is the gene for guanine nucleotide binding protein alpha stimulating (Gαs protein) activity polypeptide 1. It maps to 20q13 and belongs to an imprinted locus. Deficiency of Gαs has been associated with OHA and resistance to PTH also called pseudohypoparathyroidism (PHP1a). In addition, individuals with isolated OHA, GNAS1 lesions but absence of hormonal resistance are identified (pseudopseudohypoparathyroidism or PPHP). Maternal transmission of the hormonal resistance was demonstrated while paternal transmission was associated with PPHP.
We identified heterozygous inactivating GNAS1 mutations in 41 patients (24 females and 17 males) presenting with AHO or PHP1a. 5 patients (2 girls and 3 boys) from 5 different families were diagnosed with POH. Two patients were diagnosed during the first yr with ossified areas coalescing into plaques. These patients lack features of AHO. Gs activity and hormonal parameters are under investigations.
Segregation analysis indicated that 4 mutations had occurred de novo and one was paternally transmitted. Two mutations have been previously described either in POH, 345insT (codon 115 in exon 5) or in PHP1a, Q29X in exon 1, which was carried by two patients. We found two new mutations: 624insT in exon 8 at codon 209 and IVS121G>A (intron 12). In all cases these mutations cause premature termination of translation and loss of protein function.
This finding extends the range of phenotype derived from haploinsuffisance of GNAS1. Evidence that same mutation can cause either AHO or POH makes genetics counselling not easy.
01 - 05 Apr 2006
European Society of Endocrinology