Novel mutations of the PRKAR1A gene in patients with acrodysostosis

Abstract

Acrodysostosis is characterized by a peripheral dysostosis that is accompanied by short stature, midface hypoplasia, and developmental delay. Recently, it was shown that heterozygous point mutations in the PRKAR1A gene cause acrodysostosis with hormone resistance. By mutational analysis of the PRKAR1A gene we detected four different mutations (p.Arg368Stop, p.Ala213Thr, p.Tyr373Cys, and p.Arg335Cys) in four of seven affected patients with acrodysostosis. The combination of clinical results, endocrinological parameters and in silico mutation analysis gives evidence to suppose a pathogenic effect of each mutation. This assumption is supported by the de novo origin of these mutations. Apart from typical radiological abnormalities of the hand bones, elevated thyroid stimulating hormone and parathyroid hormone values as well as short stature are the most common findings. Less frequent features are characteristic facial dysmorphisms, sensorineural hearing loss and mild intellectual disability. These results lead to the conclusion that mutations of PKRAR1A are the major molecular cause for acrodysostosis with endocrinological abnormalities. In addition, in our cohort of 44 patients affected with brachydactyly type E (BDE) we detected only one sequence variant of PRKAR1A (p.Asp227Asn) with an unclear effect on protein function. Thus, we conclude that PRKAR1A mutations may play no major role in the pathogenesis of BDE.

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.…”

“…At the bottom, the electropherograms of missense mutations found in our series are compared with wild-type reference sequences. (16) conserved positions of the RIa subunit (Arg335 in the PBC-B and Tyr373, subject to phosphorylation, in an interaction site with PKA), thus playing a key functional role. 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.…”

“…(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.…”