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

Abstract

Purpose We 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). Methods Variants 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. Results Recent 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. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

Phenotypic characterization of seven individuals with Marbach–Schaaf neurodevelopmental syndrome

“…Among the six verbal patients, first words were spoken at an average age of 23.8 months (SD 7.6 months), and patient #4 and #7 acquired fluent speech. Regression of motor skills was observed in one male patient (patient #1) beginning at the age of 6 months, which may resemble earlier reports of two male patients of the first cohort who lost previously acquired skills (Marbach et al, 2021). Among the two adolescent patients #3 and #7, the onset of puberty was delayed in patient #3 and normal in patient #7.…”

“…If this holds true, PKA complexes containing mutant R1β would be less sensitive to rising cAMP concentrations, affecting cellular signaling downstream of PKA in PRKAR1B-expressing cells of the CNS. This theory would be consistent with the observation of reduced cAMP-stimulated (total) PKA activity in HEK293 cells transfected with a PRKAR1B p.Arg335Trp expression construct, compared to cells transfected with the wild type PRKAR1B construct, although this reduction was not statistically significant (p = 0.06;Marbach et al, 2021).Possible disturbances of several PKA-dependent functions could contribute to the reduced sensitivity to pain in most patients carrying the p.(Arg335Trp) variant, although it is currently unknown whether these pathways obligatory require the R1β subunit. For example, Gs alpha subunit (Gα s ) signaling via adenylyl cyclase/cAMP/PKA in response to pain, itch, and inflammation could be impaired, resulting in reduced sensitization of transient receptor potential channels (TRP)…”

“…The R1β subunit is highly expressed in the central nervous system (CNS), and expression during embryonal development of the human brain could be demonstrated by RNAscope imaging at Carnergie stage 22 (estimated postfertilization age of 52-55 days). Functional studies found reduced basal PKA kinase activity in HEK293 cells transfected with PRKAR1B constructs harboring variants identified in patients from the initial publication (Marbach et al, 2021).…”

“…(Arg335Trp) variant, insensitivity to pain of varying degree was reported. The patients showed behavioral abnormalities associated with autism spectrum disorder (ASD), such as arm/hand flapping, repetitive, and sensory-seeking behavior (Marbach et al, 2021). ASD was diagnosed based on DSM-5 criteria in all of the patients of that initial cohort, and four patients were diagnosed with attention deficit hyperactivity disorder (ADHD).…”

RNA sequencing profiling of mRNAs, long noncoding RNAs, and circular RNAs in Trigeminal Ganglion following Temporomandibular Joint inflammation

“…Consistent with previous reports, the levels of the GPCRs, such as Htr6 (Liu et al, 2019), Prkcd (He et al, 2016), Avp (Yang et al, 2019), Rgs3 (Doyen et al, 2017), and Npy2r (Chen et al, 2019), in the TG were remarkably increased after CFA injection. In contrast, the amounts of GPCR Prkar1b (Marbach et al, 2021), P2ry12 (Defaye et al, 2021), andHtr2c (Brasch-Andersen et al, 2011) in the TG were dramatically decreased after CFA injection. For the ion channels, we observed that the noticeably elevated expression of Rapgef3 (Liu et al, 2021), Nos1 (Shnayder et al, 2021), TRPM8 (Weyer and Lehto, 2017), and CXCL12 (Luo et al, 2016) in the TG were remarkably increased after CFA injection.…”