No evidence for GNAS copy number variants in patients with features of Albright's hereditary osteodystrophy and abnormal platelet Gs activity

Abstract

Albright's hereditary osteodystrophy (AHO) is characterized by short stature, round face, calcifications, obesity, brachydactyly and intellectual disability. AHO without hormone resistance is called pseudopseudohypoparathyroidism (PPHP), a rare clinical condition difficult to diagnose with highly variable features. PPHP is caused by paternally inherited loss-of-function mutations in the GNAS. Patients with 2q37 microdeletions or HDAC4 mutations are also defined as having an AHO-like phenotype with normal stimulatory G (Gs) function. We have studied 256 patients with AHO features but no other diagnosis. Their platelet Gs activity was determined via the aggregation-inhibition test showing Gs hypo-or hyperfuncton in 24% and 15% of the patients, respectively. Before initiating with detailed (epi)genetic GNAS studies, we here wanted to excluded copy number variants (CNVs) in GNAS as cause of AHO with a novel large-scale screening technique. Multiplex amplicon quantification (MAQ) for CNVs screening was developed for the 20q13.3 region including GNAS and potential long-range imprinting control elements such as STX16. This is the first large-scale GNAS CNV study in patients with common AHO features but no CNVs were detected. In conclusion, CNVs in the GNAS region are not likely to cause an AHO-like phenotype with or without abnormal platelet Gs activity. Future studies will be undertaken to find out whether these AHO patients with abnormal Gs function are characterized by GNAS coding or methylation defects.

Methylation Defect in Imprinted Genes Detected in Patients with an Albright's Hereditary Osteodystrophy Like Phenotype and Platelet Gs Hypofunction

“…All patients were heterozygous for at least one of the studied GNAS region SNPs, excluding small chromosomal deletions within the GNAS cluster ( Table S1 ). In addition, patients 5 to 17 were previously studied for copy number variants within the GNAS locus or its surrounding region and found to be negative [44] .…”

GNAS1 mutation analysis in gastrointestinal tumors

“…As a vital parameter in cellular signaling Gsa is ubiquitously found [7]. Different diseases are described with gain-of-function and loss-of-function mutations such as McCune-Albright-Syndrome, a disease which combines café-au-lait spots, polyostotic fibrous dysplasia and endocrinopathies [8], fibrous dysplasia itself [9] or endocrinological diseases like pseudohypoparathyroidism [10] with various mutation hotspots [11]. How imprinting mechanism of this gene leads to different diseases partly depending on parent's gender, is not totally understood [5].…”

Impaired iloprost-induced platelet inhibition and phosphoproteome changes in patients with confirmed pseudohypoparathyroidism type Ia, linked to genetic mutations in GNAS

“…On the other hand, in the related disorder pseudopseudohypoparathyroidism (PPHP), mutations in the GNAS locus occur, which are usually paternally inherited and are designated as non-AHO. www.nature.com/scientificreports/ Molecular diagnosis of these syndromes is further complicated, as an AHO phenotype can also be accompanied by normal or hyper-activity of the Gsα protein 29 . Because of this complexity, platelet phenotyping for aberrant Gαs activity may assist in diagnosis.…”