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DOI: 10.1055/s-0032-1304252
Identification of a Recurrent Mutation in the PRKAR1A Gene in Patients Affected with Chondrodysplasia and Hormone Resistance
Acrodysostosis (OMIM no. 101800) is a rare form of skeletal dysplasia with severe brachydactyly, facial dysostosis, nasal hypoplasia, and short stature. Several features of acrodysostosis are also present in patients with Albright hereditary osteodystrophy that characterizes pseudohypoparathyroidism type Ia (PHP1a), caused by loss of function mutations in the gene encoding GNAS. As described for PHP1a, resistance to either parathyroid hormone or thyrotropin has been suspected in some patients with acrodysostosis. We identified a germline recurrent de novo heterozygous mutation in the PRKAR1A gene, coding for the major regulatory subunit of the cAMP-dependent protein kinase (PKA) in three patients who presented with acrodysostosis and multiple hormonal resistance. The mutation causes PRKAR1A gain-of-function, which therefore represses constitutively the catalytic subunit and results in PKA insensitivity to cAMP. These results explain the phenotype of the patients, and the similarities with PHP1a, and will be the subject of the presentation.