Exome Sequencing Identifies PDE4D Mutations as Another Cause of Acrodysostosis

Abstract

Acrodysostosis is a rare autosomal-dominant condition characterized by facial dysostosis, severe brachydactyly with cone-shaped epiphyses, and short stature. Moderate intellectual disability and resistance to multiple hormones might also be present. Recently, a recurrent mutation (c.1102C>T [p.Arg368*]) in PRKAR1A has been identified in three individuals with acrodysostosis and resistance to multiple hormones. After studying ten unrelated acrodysostosis cases, we report here de novo PRKAR1A mutations in five out of the ten individuals (we found c.1102C>T [p.Arg368(∗)] in four of the ten and c.1117T>C [p.Tyr373His] in one of the ten). We performed exome sequencing in two of the five remaining individuals and selected phosphodiesterase 4D (PDE4D) as a candidate gene. PDE4D encodes a class IV cyclic AMP (cAMP)-specific phosphodiesterase that regulates cAMP concentration. Exome analysis detected heterozygous PDE4D mutations (c.673C>A [p.Pro225Thr] and c.677T>C [p.Phe226Ser]) in these two individuals. Screening of PDE4D identified heterozygous mutations (c.568T>G [p.Ser190Ala] and c.1759A>C [p.Thr587Pro]) in two additional acrodysostosis cases. These mutations occurred de novo in all four cases. The four individuals with PDE4D mutations shared common clinical features, namely characteristic midface and nasal hypoplasia and moderate intellectual disability. Metabolic screening was normal in three of these four individuals. However, resistance to parathyroid hormone and thyrotropin was consistently observed in the five cases with PRKAR1A mutations. Finally, our study further supports the key role of the cAMP signaling pathway in skeletogenesis.

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

“…Because the association between PRKAR1A defects and ACRDYS represents a recent discovery, the number of recurrent mutations will likely increase because some mutations, affecting key amino acids, were found to recur in unrelated subjects. (11,14,16,19) Although most of known PRKAR1A mutations alter the NBD-B (76.5%), our findings support the previous observation that mutations also affecting the NBD-A (23.5%) may be associated with ACRDYS. (13,16,pt A1) We also cross-referenced mutations associated with ACRDYS with those associated to Carney Complex, and we did not find any molecular overlap, suggesting that different substitutions lead to different and opposite effects on protein function, with consequent different clinical phenotypes.…”

“…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.…”

“…(14,19) In addition, our analysis highlighted the presence of 2 amino acid residues, arginine 335 and tyrosine 373, that may be considered as putative mutational hot spots, being mutated in 5 unrelated patients through 5 different genetic variations (c.1003C>T, c.1004G>C, c.1004G>T, c.1117T>C, and c.1118A>G) changing Arg to Cys/Pro/Leu and Tyr to His/Cys (Table 2). (11,14,16) These amino acids are located in highly Fig. 2.…”

“…(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.…”