Paternal uniparental isodisomy of the entire chromosome 20 as a molecular cause of pseudohypoparathyroidism type Ib (PHP-Ib)

• Published in: Bone (New York, N.Y.) N.Y.), 2011-03, Vol.48 (3), p.659-662
• Main Authors: Bastepe, Murat, Altug-Teber, Özge, Agarwal, Chhavi, Oberfield, Sharon E, Bonin, Michael, Jüppner, Harald
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Case reports; Child; Child, Preschool; chromosome 20; Chromosomes, Human, Pair 20 - genetics; Disease Progression; Endocrinopathies; Female; Follow-Up Studies; Fundamental and applied biological sciences. Psychology; Genomes; Hormones; Humans; Imprinting; Male; Medical sciences; Methylation; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Orthopedics; Osteodystrophy; Parathyroid hormone; Parathyroids. Parafollicular cells. Cholecalciferol. Phosphocalcic homeostasis (diseases); Pedigree; Pseudohypoparathyroidism; Pseudohypoparathyroidism - genetics; Single-nucleotide polymorphism; Uniparental Disomy - genetics; Vertebrates: anatomy and physiology, studies on body, several organs or systems
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2010.10.168

Abstract Pseudohypoparathyoridism type Ib (PHP-Ib) typically defines the presence of end-organ resistance to parathyroid hormone in the absence of Albright's hereditary osteodystrophy. Patients affected by this disorder present with imprinting defects in the complex GNAS locus. Microdeletions within STX16 or GNAS have been identified in familial cases with PHP-Ib, but the molecular cause of the GNAS imprinting defects in sporadic PHP-Ib cases remains poorly defined. We now report a case with sporadic PHP-Ib for whom a SNPlex analysis revealed loss of the maternal GNAS allele. Further analysis of the entire genome with a 100 K SNP chip identified a paternal uniparental isodisomy affecting the entire chromosome 20 without evidence for another chromosomal abnormality. Our findings explain the observed GNAS methylation changes and the patient's hormone resistance, and furthermore suggest that chromosome 20 harbors, besides GNAS, no additional imprinted region that contributes to the clinical and laboratory phenotype.