Variants inPRKAR1Bcause a neurodevelopmental disorder with autism spectrum disorder,apraxia, and insensitivity to pain

Abstract

Purpose: We characterize the phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder, who carry heterozygous missense-variants of the PRKAR1B gene. Methods: Variants of PRKAR1B were identified by single-exome or trio-exome analysis. We contacted the families and physicians of the six individuals in order to collect clinical and phenotypic information. Results: PRKAR1B encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA), and is predominantly expressed in the central nervous system. Recent studies of patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B, and in vivo studies of the murine ortholog demonstrated altered hippocampal function and reduced neurogenic inflammation and long-term nociceptive pain in R1β-deficient mice. In our study, de novo origin of the PRKAR1B-variants could be confirmed in five out 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 has been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. Conclusion: Our study provides strong evidence for a novel, 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).…”

“…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).…”

“…In the case of patients carrying the recurring NM_001164760.2: c.1003C>T p.(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).…”

High-dimensional phenotyping to define the genetic basis of cellular morphology

“…rs36036340 lies within the gene PRKAR1B. Variants in PRKAR1B have been linked to neurodevelopmental disorders and activity of PRKAR1B has been shown to regulate tumorigenesis [39][40][41] . PRKAR1B mediates PI3K/AKT/mTOR pathway signaling through direct interactions between PRKAR1B and PI3K-110alpha 39 .…”