Phenotype–genotype correlations in patients with GNB1 gene variants, including the first three reported Japanese patients to exhibit spastic diplegia, dyskinetic quadriplegia, and infantile spasms

Endo, Wakaba; Ikemoto, Satoru; Togashi, Noriko; Miyabayashi, Takuya; Nakajima, Erika; Hamano, Shin ichiro; Shibuya, Moriei; Sato, Ryo; Takezawa, Yusuke; Okubo, Yukimune; Inui, Tomoyuki; Kato, Mitsuhiro; Sengoku, Toru; Ogata, Kazuhiro; Hamanaka, Kohei; Mizuguchi, Takeshi; Miyatake, Satoko; Nakashima, Mitsuko; Matsumoto, Naomichi; Haginoya, Kazuhiro

doi:10.1016/j.braindev.2019.10.006

Cited by 20 publications

(33 citation statements)

References 15 publications

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“…We found that one Gprotein subunit, GNB1, was significantly decreased in all the regions. Missense, splice-site and frameshift variants in the GNB1 gene are associated with multiple neurological phenotypes, including seizures in most cases [75][76][77][78][79][80]. Mice harboring the GNB1 K78R human pathogenic recapitulate many clinical features, including developmental delay, motor and cognitive deficits, and absence-like generalized seizures, and that cellular models displayed extended bursts of firing followed by extensive recovery periods [81].…”

Section: Discussionmentioning

confidence: 99%

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Pires

Leitner

Drummond

et al. 2020

Preprint

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Epilepsy is a common neurological disorder affecting over 70 million people worldwide, with a high rate of pharmaco-resistance, diverse comorbidities including progressive cognitive and behavioral disorders, and increased mortality from direct (e.g., Sudden Unexpected Death in Epilepsy [SUDEP], accidents, drowning) or indirect effects of seizures and therapies. Extensive research with animal models and human studies provides limited insights into the mechanisms underlying seizures and epileptogenesis, and these have not translated into significant reductions in pharmaco-resistance, morbidities or mortality. To help define changes in molecular signaling networks associated with epilepsy, we examined the proteome of brain samples from epilepsy and control cases. Label-free quantitative mass spectrometry (MS) was performed on the hippocampal CA1-3 region, frontal cortex, and dentate gyrus microdissected from epilepsy and control cases (n=14/group). Epilepsy cases had significant differences in the expression of 777 proteins in the hippocampal CA1-3 region, 296 proteins in the frontal cortex, and 49 proteins in the dentate gyrus in comparison to control cases. Network analysis showed that proteins involved in protein synthesis, mitochondrial function, G-protein signaling, and synaptic plasticity were particularly altered in epilepsy. While protein differences were most pronounced in the hippocampus, similar changes were observed in other brain regions indicating broad proteomic abnormalities in epilepsy. Among the most significantly altered proteins, G-protein Subunit Beta 1 (GNB1) was one of the most significantly decreased proteins in epilepsy in all regions studied, highlighting the importance of G-protein subunit signaling and G-protein–coupled receptors (GPCRs) in epilepsy. Our results provide insights into the molecular mechanisms underlying epilepsy, which may allow for novel targeted therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Pires

Leitner

Drummond

et al. 2020

Preprint

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“…Homozygous loss of Gnb1 in mice is embryonically lethal with affected embryos showing abnormal brain morphology and defects in neural precursor differentiation and proliferation (Okae & Iwakura, 2010). In humans, variants in this gene have been associated with a neurodevelopmental disorder (NDD; OMIM: 616973, Mental retardation, autosomal dominant 42) with patients presenting with global developmental delay, hypotonia, and epilepsy (Brett et al, 2017; Endo et al, 2020; Hemati et al, 2018; Jones et al, 2019; Lohmann et al, 2017; Peng et al, 2019; Petrovski et al, 2016; Steinrucke et al, 2016; Szczaluba et al, 2018). Other prevalent phenotypes reported include brain abnormalities, ophthalmological disorders, growth restriction, movement disorders, and non‐specific dysmorphisms (Revah‐Politi, Sands, Colombo, Goldstein, & Anyane‐Yeboa, 1993).…”

Section: Introductionmentioning

confidence: 99%

Haploinsufficiency as a disease mechanism in GNB1‐associated neurodevelopmental disorder

Schultz‐Rogers

Masuho

Vairo

et al. 2020

Molec Gen & Gen Med

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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

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“…To date, only the most commonly mutated residue, p.Ile80, has proposed genotype-phenotype correlations: p.Ile80Thr and cutaneous mastocytosis (Hemati et al, 2018); p.Ile80Thr and severe axial hypotonia or hypotonic quadriplegia; and p.Ile80Thr or p.Ile80Asn and dystonia (Endo et al, 2020;Revah-Politi et al, 2020). We report a potential novel genotype-phenotype correlation of a different recurrent variant, c.284T > C (p.Leu95Pro), which has been reported in four patients (Endo et al, 2020;Hemati et al, 2018;Petrovski et al, 2016).…”

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confidence: 99%

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

Lansdon

Saunders

2021

American J of Med Genetics Pt A

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Heterozygous variants in G protein subunit beta 1 (GNB1) are associated with a broad and severe neurodevelopmental phenotype (MIM: 616973) characterized by moderate to severe global developmental delay in all patients as well as variable neurological features which frequently include abnormal muscle tone (hypotonia evolving to hypertonia and spasticity), abnormal vision, and epilepsy. More than half of patients are non-ambulatory and nonverbal. Other findings include gastrointestinal and ophthalmological anomalies, genitourinary anomalies in males, persistent growth delay, dystonia, and abnormal vision (optic atrophy, cortical visual impairment, strabismus, and nystagmus).

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Phenotype–genotype correlations in patients with GNB1 gene variants, including the first three reported Japanese patients to exhibit spastic diplegia, dyskinetic quadriplegia, and infantile spasms

Cited by 20 publications

References 15 publications

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Haploinsufficiency as a disease mechanism in GNB1‐associated neurodevelopmental disorder

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

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