The First Mutation Identified in a Chinese Acrodysostosis Patient Confirms a p.G289E Variation of PRKAR1A Causes Acrodysostosis

Abstract

Acrodysostosis is a rare skeletal dysplasia, which has not been reported previously in patients of Chinese origin. The PRKAR1A gene and PDE4D gene have been found to be causative genes of acrodysostosis. A Chinese girl with acrodysostosis and concomitant multiple hormone resistance was recruited for our study. Clinical and biochemical characters were analyzed. DNA was extracted from leukocytes and was sequenced for GNAS, PDE4D and PRKAR1A gene mutations. A de novo heterozygous missense mutation (c.866G>A/p.G289E) was identified in the PRKAR1A gene. This mutation coincided with a mutation that had been found in a patient from another ethnic group. Our findings further suggest that the c.866G>A/p.G289E mutation in the PRKAR1A gene may be the cause of acrodysostosis with concomitant multiple hormone resistance. Moreover, it is the first report of acrodysostosis genetic analysis of Chinese origin.

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.…”

“…To predict the possible in vivo effect of novel PRKAR1A and PDE4D genetic defects detected in our series, we performed an extensive review of published data and an in silico analysis using different computer-generated algorithms. (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) In silico analyses aren't a substitute for functional studies in determining the pathogenicity of a genetic variant but allow the evaluation of the impact of mutations on the protein product, based on combined analysis of protein multiple sequence alignment and protein structural and functional attributes. In particular, we used the following algorithms: polymorphism phenotyping program 2 (Polyphen2; available at http://genetics.bwh.harvard.…”

“…(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.…”

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

“…Brachydactyly develops over time and might not be evident in early life, except in patients with acrodysostosis 6,35,86 . The frequency and severity of brachydactyly vary among the different disorders: 70-80% in PHP1A 51 , 15-33% in PHP1B 46,51,70,[87][88][89][90][91][92][93] and all patients with acrodysostosis 5,6,14,15,20,[62][63][64][94][95][96] (Table 1). However, brachydactyly is not specific to PHP and related disorders and can be found in patients with, for example, tricho-rhino-phalangeal syndrome, brachydactyly mental retardation syndrome or Turner syndrome (Table 2).…”