PRKAR1A mutation affecting cAMP-mediated G protein-coupled receptor signaling in a patient with acrodysostosis and hormone resistance.
BACKGROUND
Acrodysostosis is a rare autosomal dominant disorder characterized by short stature, peculiar facial appearance with nasal hypoplasia, and short metacarpotarsals and phalanges with cone-shaped epiphyses. Recently, mutations of PRKAR1A and PDE4D downstream of GNAS on the cAMP-mediated G protein-coupled receptor (GPCR) signaling cascade have been identified in acrodysostosis with and without hormone resistance, although functional studies have been performed only for p.R368X of PRKAR1A.


OBJECTIVE
Our objective was to report a novel PRKAR1A mutation and its functional consequence in a Japanese female patient with acrodysostosis and hormone resistance.


METHODS
This patient had acrodysostosis-compatible clinical features such as short stature and brachydactyly and mildly elevated serum PTH and TSH values.


RESULTS
Although no abnormality was detected in GNAS and PDE4D, a novel de novo heterozygous missense mutation (p.T239A) was identified at the cAMP-binding domain A of PRKAR1A. Western blot analysis using primary antibodies for the phosphorylated cAMP-responsive element (CRE)-binding protein showed markedly reduced CRE-binding protein phosphorylation in the forskolin-stimulated lymphoblastoid cell lines of this patient. CRE-luciferase reporter assays indicated significantly impaired response of protein kinase A to cAMP in the HEK293 cells expressing the mutant p.T239A protein.


CONCLUSIONS
The results indicate that acrodysostosis with hormone resistance is caused by a heterozygous mutation at the cAMP-binding domain A of PRKAR1A because of impaired cAMP-mediated GPCR signaling. Because GNAS, PRKAR1A, and PDE4D are involved in the GPCR signal transduction cascade and have some different characters, this would explain the phenotypic similarity and difference in patients with GNAS, PRKAR1A, and PDE4D mutations.
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.
Keisuke
K
Nagasaki
Tomoko
T
Iida
Hidetoshi
H
Sato
Yohei
Y
Ogawa
Toru
T
Kikuchi
Akihiko
A
Saitoh
Tsutomu
T
Ogata
Maki
M
Fukami
D015153:Blotting, Western; D001827:Body Height / Q000235:genetics; D059327:Brachydactyly / Q000235:genetics; D045744:Cell Line, Tumor; D002675:Child, Preschool; D000242:Cyclic AMP / Q000502:physiology*; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004413:Dysostoses / Q000235:genetics*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D009154:Mutation / Q000235:genetics* / Q000502:physiology*; D020125:Mutation, Missense / Q000235:genetics; D010009:Osteochondrodysplasias / Q000235:genetics*; D010281:Parathyroid Hormone / Q000097:blood; D010766:Phosphorylation; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013972:Thyrotropin / Q000097:blood; D014162:Transfection
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D010281:Parathyroid Hormone; D043562:Receptors, G-Protein-Coupled; D013972:Thyrotropin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human