Format

Send to

Choose Destination
See comment in PubMed Commons below
J Clin Endocrinol Metab. 2012 Sep;97(9):E1808-13. doi: 10.1210/jc.2012-1369. Epub 2012 Jun 20.

PRKAR1A mutation affecting cAMP-mediated G protein-coupled receptor signaling in a patient with acrodysostosis and hormone resistance.

Author information

1
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.

Abstract

CONTEXT:

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.

PATIENT:

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.

PMID:
22723333
DOI:
10.1210/jc.2012-1369
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Silverchair Information Systems
    Loading ...
    Support Center