Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

Felix Marbach,Christina G.S Palmer,Susanne Theiß,Richard Person,Julian A Martínez‐Agosto ,Yuhua Cheng ,Chad R Haldeman-Englert ,Aaron Sievers,Evgenia Sklirou,Panagiotis Katsonis,Dorothy K Grange,Olivier Lichtarge,Nikolaos Settas,E Kessler ,Magdalena Laugsch,Constantine A Stratakis,Rebecca Willaert,Stanley F Nelson,Amber Stocco,Edra London,Jill A Rosenfeld,Aida Telegrafi,Georgi Stoyanov,Marisa V Andrews,Florian Erger,Erin Torti,Rebecca Signer ,Sophia Ceulemans,Christian P Schaaf

doi:10.1038/s41436-021-01152-7

Abstract

PurposeWe characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). MethodsVariants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. ResultsRecent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. ConclusionOur study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

Highlights

The gene PRKAR1B (Protein Kinase cAMP-Dependent Type I Regulatory Subunit Beta) encodes a regulatory subunit of the cyclic AMP-dependent protein kinase A protein complex (PKA), which is a nearly universal cellular component in eukaryotes.[1]
This study presents a systematic characterization of a neurodevelopmental disorders (NDDs) associated with missense variants in PRKAR1B
In addition to the observed enrichment of de novo missense variants of this gene in two large, independent cohorts of individuals with NDDs,[15,16] the recurrent finding of the de novo variant c.1003C>T in phenotypically similar individuals strongly suggests that this variant is causative for the observed phenotype, and indicates a potential mutational hotspot in the Arg[335] residue

Summary

Introduction

The gene PRKAR1B (Protein Kinase cAMP-Dependent Type I Regulatory Subunit Beta) encodes a regulatory subunit of the cyclic AMP-dependent protein kinase A protein complex (PKA), which is a nearly universal cellular component in eukaryotes.[1]. The genes PRKAR1A, PRKAR1B, PRKAR2A, and PRKAR2B encode the regulatory subunits RIα, RIβ, RIIα, and RIIβ, while the genes PRKCA and PRKCB give rise to a total of six principal catalytic subunit isoforms: Cα1, Cα2, and Cβ1–4. Cell type–specific expression of different subunits changes the composition and thereby intracellular localization and substrate specificity of PKA isoforms.[2] R subunits serve as cAMP receptors and facilitate the spatial localization of PKA within the cell by binding different A-Kinase anchoring proteins (AKAPs).[3] The subunit RIβ is primarily expressed in the brain,[4,5] with the highest levels of expression in the cerebral cortex and hypothalamus.[6]

Methods

Results

Conclusion