1) J Clin Endocrinol Metab. 2010 Jun;95(6):3028-3038. Epub 2010 Apr 28.
Progressive Osseous Heteroplasia: A Model for the Imprinting Effects of GNAS Inactivating Mutations in Humans.

Lebrun M, Richard N, Abeguilé G, David A, Dieux AC, Journel H, Lacombe D, Pinto G, Odent S, Salles JP, Taieb A, Gandon-Laloum S, Kottler ML.

Centre Hospitalier Universitaire Clemenceau, Département Génétique et Reproduction, Génétique Moléculaire, 14033 Caen cedex, France. kottler-ml@chu-caen.fr .


Context: Heterozygous GNAS inactivating mutations are known to induce pseudohypoparathyroidism type 1a when maternally inherited and pseudopseudohypoparathyroidism when paternally inherited. Progressive osseous heteroplasia (POH) is a rare disease of ectopic bone formation, and studies in different families have shown that POH is also caused by paternally inherited GNAS mutations. Objective: Our purpose was to characterize parental origin of the mutated allele in de novo cases of POH and to draw phenotype/genotype correlations according to maternal or paternal transmission of a same GNAS mutation. Design and Setting: We conducted a retrospective study on patients addressed to our referral center for the rare diseases of calcium and phosphorus metabolism. Patients and Methods: We matched 10 cases of POH with cases of pseudohypoparathyroidism type 1a carrying the same GNAS mutations. Main Outcome Measures: The parental origin of the mutated allele was studied using informative intragenic polymorphisms and subcloning of PCR products. Results: Paternal origin of GNAS mutations was clearly demonstrated in eight POH cases including one patient with mutation in exon 1. Genotype/phenotype analyses suggest that there is no direct correlation between the ossifying process and the position of the inactivating GNAS mutation. It is, however, more severe in patients in whom origin of the mutation is paternal. Severe intrauterine growth retardation was clearly evidenced in paternally inherited mutations. Conclusions: Clinical heterogeneity makes genetic counseling a delicate matter, especially in which paternal inheritance is concerned because it can lead to either a mild expression of pseudopseudohypoparathyroidism or a severe expression of POH.

PMID: 20427508 [PubMed – as supplied by publisher]

2) J Pediatr Endocrinol Metab. 2010 Mar;23(3):303-9.
Progressive osseous heteroplasia caused by a novel nonsense mutation in the GNAS1 gene.

Goto M, Mabe H, Nishimura G, Katsumata N.

Department of Pediatrics, Tokyo Metropolitan Hachioji Children’s Hospital, Hachioji, Japan. mgoto@chp.hachioji.tokyo.jp

Progressive osseous heteroplasia (POH), characterized by progressive heterotopic ossifications of the dermis, skeletal muscle and deep connective tissues, is caused by inactivating mutations of GNAS1 of a paternally transmitted allele. We report a novel GNAS1 mutation in a patient with POH. The patient is a 6-year-old boy, whose short stature came to medical attention in infancy. He was diagnosed with growth hormone (GH) deficiency, and subsequent GH therapy resulted in catch-up growth. He developed soft tissue masses in the right heel and right elbow that were calcified or ossified on plain radiographs. MR imaging raised a suspicion of heterotopic ossification; thus, GNAS1 was analyzed. A novel nonsense mutation p.R342X was observed in the patient, but not in his parents. Single nucleotide polymorphism analysis revealed paternal transmission of the mutant allele. RT-PCR analysis demonstrated expression of both normal and mutant GNAS1 transcripts in the patient. Thus, the patient is considered to have developed POH because of the non-functioning truncated Gs(alpha) protein.

PMID: 20480732 [PubMed – indexed for MEDLINE]