Screening of PRKAR1A and PDE4D in a Large Italian Series of Patients Clinically Diagnosed with Albright Hereditary Osteodystrophy and/or Pseudohypoparathyroidism

Francesca Marta Elli, Paolo Bordogna, Luisa De Sanctis, Federica Giachero, Elisa Verrua, Maria Segni, Laura Mazzanti, Valentina Boldrin, Alma Toromanovic, Anna Spada, Giovanna Mantovani

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The cyclic adenosine monophosphate (cAMP) intracellular signaling pathway mediates the physiological effects of several hormones and neurotransmitters, acting by the activation of G-protein coupled receptors (GPCRs) and several downstream intracellular effectors, including the heterotrimeric stimulatory G-protein (Gs), the cAMP-dependent protein kinase A (PKA), and cAMP-specific phosphodiesterases (PDEs). Defective G-protein-mediated signaling has been associated with an increasing number of disorders, including Albright hereditary osteodistrophy (AHO) and pseudohypoparathyroidism (PHP), a heterogeneous group of rare genetic metabolic disorders resulting from molecular defects at the GNAS locus. Moreover, mutations in PRKAR1A and PDE4D genes have been recently detected in patients with acrodysostosis (ACRDYS), showing a skeletal and endocrinological phenotype partially overlapping with AHO/PHP. Despite the high detection rate of molecular defects by currently available molecular approaches, about 30% of AHO/PHP patients still lack a molecular diagnosis, hence the need to screen patients negative for GNAS epi/genetic defects also for chromosomal regions and genes associated with diseases that undergo differential diagnosis with PHP. According to the growing knowledge on Gsα-cAMP signaling-linked disorders, we investigated our series of patients (n = 81) with a clinical diagnosis of PHP/AHO but negative for GNAS anomalies for the presence of novel genetic variants at PRKAR1A and PDE4D genes. Our work allowed the detection of 8 novel missense variants affecting genes so far associated with ACRDYS in 9 patients. Our data further confirm the molecular and clinical overlap among these disorders. We present the data collected from a large series of patients and a brief review of the literature in order to compare our findings with already published data; to look for PRKAR1A/PDE4D mutation spectrum, recurrent mutations, and mutation hot spots; and to identify specific clinical features associated with ACRDYS that deserve surveillance during follow-up.

Original languageEnglish
Pages (from-to)1215-1224
Number of pages10
JournalJournal of Bone and Mineral Research
Volume31
Issue number6
DOIs
Publication statusPublished - Jun 1 2016

Fingerprint

Pseudohypoparathyroidism
Cyclic AMP
Mutation
Genes
Gs GTP-Binding Protein alpha Subunits
Heterotrimeric GTP-Binding Proteins
Inborn Genetic Diseases
Phosphoric Diester Hydrolases
G-Protein-Coupled Receptors
Cyclic AMP-Dependent Protein Kinases
GTP-Binding Proteins
Neurotransmitter Agents
Albright's hereditary osteodystrophy
Differential Diagnosis
Hormones
Phenotype
Acrodysostosis

Keywords

  • ACRODYSOSTOSIS
  • AHO
  • GNAS
  • PDE4D
  • PRKAR1A

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Screening of PRKAR1A and PDE4D in a Large Italian Series of Patients Clinically Diagnosed with Albright Hereditary Osteodystrophy and/or Pseudohypoparathyroidism. / Elli, Francesca Marta; Bordogna, Paolo; De Sanctis, Luisa; Giachero, Federica; Verrua, Elisa; Segni, Maria; Mazzanti, Laura; Boldrin, Valentina; Toromanovic, Alma; Spada, Anna; Mantovani, Giovanna.

In: Journal of Bone and Mineral Research, Vol. 31, No. 6, 01.06.2016, p. 1215-1224.

Research output: Contribution to journalArticle

Elli, FM, Bordogna, P, De Sanctis, L, Giachero, F, Verrua, E, Segni, M, Mazzanti, L, Boldrin, V, Toromanovic, A, Spada, A & Mantovani, G 2016, 'Screening of PRKAR1A and PDE4D in a Large Italian Series of Patients Clinically Diagnosed with Albright Hereditary Osteodystrophy and/or Pseudohypoparathyroidism', Journal of Bone and Mineral Research, vol. 31, no. 6, pp. 1215-1224. https://doi.org/10.1002/jbmr.2785
Elli, Francesca Marta ; Bordogna, Paolo ; De Sanctis, Luisa ; Giachero, Federica ; Verrua, Elisa ; Segni, Maria ; Mazzanti, Laura ; Boldrin, Valentina ; Toromanovic, Alma ; Spada, Anna ; Mantovani, Giovanna. / Screening of PRKAR1A and PDE4D in a Large Italian Series of Patients Clinically Diagnosed with Albright Hereditary Osteodystrophy and/or Pseudohypoparathyroidism. In: Journal of Bone and Mineral Research. 2016 ; Vol. 31, No. 6. pp. 1215-1224.
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