Haploinsufficiency as a disease mechanism in GNB1‐associated neurodevelopmental disorder

Abstract

The gene GNB1 (guanine nucleotide binding protein (G protein), beta polypeptide 1; OMIM: 616973 and OMIM:613065) encodes the Gβ subunit of a heterotrimeric G-protein complex which additionally includes Gα and Gγ subunits. This complex functions to transduce a variety of intracellular signaling cascades (Ford et al., 1998). Homozygous loss of Gnb1 in mice is embryonically lethal with affected embryos showing abnormal brain morphology and defects in neural precursor

Case Report: A Novel GNB1 Mutation Causes Global Developmental Delay With Intellectual Disability and Behavioral Disorders

“…An interesting finding is that, out of the 51 patients with pathogenic missense variants, 25 (49%) are located in exon 6, and 20 (39%) are in exon 7, indicating the presence of a mutational hotspot (1,3,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Of note, 13 patients (25%) bear a p.(Ile80Thr) variant, which further supports such hypothesis (Table 1).…”

“…Several other neuropsychiatric and nonneuropsychiatric symptoms have also been reported, albeit less frequently (3,6). Nevertheless, clinical data is very limited since only 58 patients with clinical-impacting GNB1 variants have been reported (1,3,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Moreover, this syndrome can easily overlap with many conditions, being clinically indistinguishable from other neurodevelopmental disorders.…”

Genotype–phenotype correlation in GNB1‐related neurodevelopmental disorder: Potential association of p.Leu95Pro with cleft palate

“…Cell-based assays of somatic GNB1 missense changes demonstrated these variants result in the constitutive activation of the G-protein, leading to an increase in canonical G-protein signaling (Yoda et al, 2015). In addition, recent reports characterizing the functional consequence of germline missense and nonsense variants identified in patients with GNB1-related neurodevelopmental syndrome support haploinsufficiency as a possible disease mechanism for variants originating near the C-terminus (Schultz-Rogers et al, 2020). Gnb1-knockout mouse models show Gnb1 is required for embryonic neurogenesis and neonatal development, as homozygous loss resulted in neural tube defects, abnormal neuroepithelial actin organization, microencephaly, and death within 2 days after birth (Okae & Iwakura, 2010).…”

“…reported to date either have very mild features with no commonalities or are not reported to have dysmorphic features (Brett et al, 2017;Endo et al, 2020;Hemati et al, 2018;Lohmann et al, 2017;Petrovski et al, 2016;Revah-Politi, Sands, Colombo, Goldstein, & Anyane-Yeboa, 2020;Schultz-Rogers et al, 2020;Steinrucke et al, 2016;Szczaluba et al, 2018).…”

Impaired Function of PLEKHG2, a Rho-Guanine Nucleotide-Exchange Factor, Disrupts Corticogenesis in Neurodevelopmental Phenotypes

“…Indeed, p.Arg200Trp variation was shown to abrogate the ability of Gβγ to activate Plekhg2 ( Figure 1 A–C) and PAK1 ( Figure 1 D) in COS7 cells. Considering that Gβγ is released from the heterotrimeric G proteins in responses to cell surface receptor stimulation and is associated with neurodevelopmental disorders [ 37 , 38 , 39 ], receptor-mediated signaling might play a role in neuronal morphology and synaptic plasticity. Further investigation is required to clarify the physiological significance of Gβγ-dependent Plekhg2 GEF activity for Rac/Cdc42 and subsequent PAK1 activation.…”