PRKAR1A – Acrodysostosis

Acrodysostosis (MONDO:0019797) is a rare autosomal dominant skeletal dysplasia characterized by short stature, severe brachydactyly with cone-shaped epiphyses, and facial dysostosis. Heterozygous mutations in PRKAR1A, encoding the PKA regulatory subunit R1α, disrupt cAMP-mediated GPCR signaling and underlie acrodysostosis with hormone resistance.

In multiple series, de novo heterozygous PRKAR1A variants were identified in over 30 unrelated individuals (PMID:21651393; PMID:22464250; PMID:23043190; PMID:23425300; PMID:22723333). Variant spectrum includes recurrent nonsense c.1102C>T (p.Arg368Ter), missense substitutions in cAMP-binding domains (c.854A>G (p.Gln285Arg)), and frameshift truncations.

Patients uniformly exhibit short stature (HP:0004322) and brachydactyly (HP:0001156), often accompanied by resistance to parathyroid and thyroid hormones. Craniofacial features include nasal hypoplasia and midface retrusion; mild intellectual disability may be present in some cases.

Functional assays demonstrate markedly reduced CREB phosphorylation and impaired PKA activation in patient lymphoblastoid cells and HEK293 transfectants expressing mutant R1α upon forskolin stimulation (PMID:22723333). BRET and luciferase reporter studies confirm domain-specific cAMP binding defects (PMID:26405036).

A knock-in mouse model carrying the recurrent R368X mutation recapitulates growth retardation, peripheral acrodysostosis, and hormone resistance, while AAV9-mediated human PRKAR1A gene therapy restores growth plate architecture and normalizes urinary cAMP levels (PMID:27589370; PMID:34599290).

These data establish haploinsufficiency of PRKAR1A as the mechanism of acrodysostosis, supporting molecular diagnosis, genetic counseling, and exploration of gene therapy. Key Take-home: PRKAR1A variants cause acrodysostosis via disrupted cAMP-PKA signaling, informing clinical management and potential therapeutic strategies.

References

• The New England Journal of Medicine • 2011 • Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance. PMID:21651393
• American Journal of Human Genetics • 2012 • Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis. PMID:22464250
• The Journal of Clinical Endocrinology and Metabolism • 2012 • PRKAR1A mutation affecting cAMP-mediated G protein-coupled receptor signaling in a patient with acrodysostosis and hormone resistance. PMID:22723333
• The Journal of Clinical Endocrinology and Metabolism • 2012 • PRKAR1A and PDE4D mutations cause acrodysostosis but two distinct syndromes with or without GPCR-signaling hormone resistance. PMID:23043190
• Clinical Genetics • 2013 • Novel mutations of the PRKAR1A gene in patients with acrodysostosis. PMID:23425300
• The Journal of Biological Chemistry • 2015 • Functional Characterization of PRKAR1A Mutations Reveals a Unique Molecular Mechanism Causing Acrodysostosis but Multiple Mechanisms Causing Carney Complex. PMID:26405036
• Journal of Bone and Mineral Research • 2017 • Knock-In of the Recurrent R368X Mutation of PRKAR1A that Represses cAMP-Dependent Protein Kinase A Activation: A Model of Type 1 Acrodysostosis. PMID:27589370
• Gene Therapy • 2022 • Correction of a knock-in mouse model of acrodysostosis with gene therapy using a rAAV9-CAG-human PRKAR1A vector. PMID:34599290

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