Exome Sequencing Identifies PDE4D Mutations in Acrodysostosis

Abstract

Acrodysostosis is a dominantly-inherited, multisystem disorder characterized by skeletal, endocrine, and neurological abnormalities. To identify the molecular basis of acrodysostosis, we performed exome sequencing on five genetically independent cases. Three different missense mutations in PDE4D, which encodes cyclic AMP (cAMP)-specific phosphodiesterase 4D, were found to be heterozygous in three of the cases. Two of the mutations were demonstrated to have occurred de novo, providing strong genetic evidence of causation. Two additional cases were heterozygous for de novo missense mutations in PRKAR1A, which encodes the cAMP-dependent regulatory subunit of protein kinase A and which has been recently reported to be the cause of a form of acrodysostosis resistant to multiple hormones. These findings demonstrate that acrodysostosis is genetically heterogeneous and underscore the exquisite sensitivity of many tissues to alterations in cAMP homeostasis.

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

“…1). (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) Considering the distribution of the mutations, exon 11 is the most affected site (52.9%), followed by exon 9 (23.5%), exon 7 (17.6%), and exon 8 (5.9%). No mutations were observed in other exons, acceptor-donor splice sites, and introns.…”

“…2). (11,12,14,15,17,18,20) Considering the distribution of these mutations, exon 5 is the most affected site (36%), followed by exon 15 (16%), exons 8 and 17 (12% each), exon 9 (8%), and exons 4, 6, 13, and 16 (4% each). No mutation has been observed to date in other exons, acceptor-donor splice sites, and introns.…”

“…Lee et al (12) in about 18% of PRKAR1A-mutated patients, and cryptorchidism and/or lack of pubertal spurt, possibly secondary to hormone resistance, were described in about 19% of patients with PDE4D mutations. Overall, the most frequent clinical features were brachydactyly (PRKAR1A ¼ 97% and PDE4D ¼ 92%) and dysmorphic facies (PRKAR1A ¼ 75% and PDE4D ¼ 90%).…”

“…(9) Mutations in genes encoding proteins crucial for cAMP-mediated signaling have been recently detected in a small subset of patients negative for GNAS defects, showing a phenotypic overlap between PHP and acrodysostosis. (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) The term acrodysostosis (ACRDYS) describes a group of rare skeletal disorders characterized by severe brachydactyly, nasal, and/or midfacial hypoplasia and variable intellectual/ developmental/behavioral disabilities; resistance to multiple hormones that bind to GPCRs (including PTH and TSH), progressive growth failure with short stature, advanced bone age, and obesity are frequently observed features. (21) Genetic defects affecting PRKAR1A (cAMP-dependent protein kinase type I-a regulatory subunit) and PDE4D (cAMP-specific phosphodiesterase 4D), both crucial for cAMP signaling pathway, were associated with ACRDYS in 2011 and 2012 by different research groups.…”

“…(21) Genetic defects affecting PRKAR1A (cAMP-dependent protein kinase type I-a regulatory subunit) and PDE4D (cAMP-specific phosphodiesterase 4D), both crucial for cAMP signaling pathway, were associated with ACRDYS in 2011 and 2012 by different research groups. (10)(11)(12) According to the growing knowledge on Gsa-cAMP signalinglinked disorders, we investigated our series of patients with a clinical diagnosis of PHP1A/AHO but negative for GNAS defects for the presence of novel genetic variants at PRKAR1/PDE4D genes. In particular, in the present work, we present the data collected from 9 mutated of 81 investigated cases 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 poorly investigated clinical features associated with ACRDYS, which deserve surveillance during follow-up.…”