Endocrine Abstracts

Introduction: The human GNAS gene is coding for the alpha stimulatory subunit of the guanine nucleotide-binding protein. This G protein stimulates the activity of the adenylate cyclase enzyme which is in control of the production of various hormones in endocrine glands and also regulates bone development. Mutations in GNAS can lead to McCune Albright syndrome, progressive osseous heteroplasia or pseudohypoparathyroidism.

Aim: Our aim was to find the genetic background of the disease.

Materials and methods: In this study we screened 24 people, 20 index patients and 4 relatives, 9 with preliminary McCune Albright indication and 11 with pseudohypoparathyroidism. For genetic testing peripherial blood was collected. In two cases tumor tissue samples were also available. Genomic DNA was isolated with Qiagen DNAeasy Blood and Tissue kit. PCR products were directly Sanger sequenced. Sequence data obtained were compared to NCBI and ENSEMBL databases.

Results: Out of 9 samples only one tissue (11%) tested positive for somatic mosaic (level 25–30%) mutation, p.MET703_ARG704del, thus for McCune Albright syndrome. In the case of pseudohypoparathyreosis 6 germ line mutations out of 11 index patients could be detected (54%). Inheritance of the mutations within families could be observed. In our samples one GNAS c.2277delC frameshift mutation was found in heterozygotic form possibly causing truncated protein. The heterozygous Leu706Pro probably damaging (Polyphen2 score 1.0) variant, was found in the index patient but absent in the parents, likely originated de novo. The GNAS Arg231Cys known pathogenic mutation was found in three cases, one mother and two siblings. The c.432+1G>A splice mutation could be detected in one index patien and her mother, The known pathogenic heterogeneous 4 bp deletion rs587776829 was also detected.

Discussion: Six different mutations in 6 index patients (54%) were found and symptomes could be matched to pseudohypoparathyreosis type 1a. McCune Albright syndrome found in one case only shows the importance of testing somatic DNA samples is of critical importance here.

Acknowledgements: This work has been funded by National Program of Bionics to A.P.