Alternative titles; symbols
HGNC Approved Gene Symbol: GNAI1
Cytogenetic location: 7q21.11 Genomic coordinates (GRCh38) : 7:80,134,831-80,226,181 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q21.11 | Neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities | 619854 | Autosomal dominant | 3 |
Guanine nucleotide-binding proteins (G proteins) form a large family of signal-transducing molecules. They are found as heterotrimers made up of alpha, beta, and gamma subunits. Members of the G protein family have been characterized most extensively on the basis of the alpha subunit, which binds guanine nucleotide, is capable of hydrolyzing GTP, and interacts with specific receptor and effector molecules. The G protein family includes Gs (139320) and Gi, the stimulatory and inhibitory GTP-binding regulators of adenylate cyclase; Go, a protein abundant in brain (GNAO1; 139311); and transducin-1 (GNAT1; 139330) and transducin-2 (GNAT2; 139340), proteins involved in phototransduction in retinal rods and cones, respectively (Sullivan et al., 1986; Bray et al., 1987).
Suki et al. (1987) concluded that the human genome contains at least 3 nonallelic genes for alpha-i-type subunits of G protein; see, e.g., GNAI2 (139360), GNAI3 (139370), and GNAIH (139180).
Sullivan et al. (1986) used a cDNA encoding bovine alpha chain of transducin-1 to isolate and sequence murine cDNAs for alpha(s) and alpha(i). Homologies and differences among the deduced amino acid sequences of the G protein and transducin alpha chains pointed to specific regions that may interact with guanine nucleotides, receptors, effector enzymes, and the G protein beta-gamma complex.
Bray et al. (1987) isolated cDNA clones corresponding to the alpha(i) subunit from a human brain cDNA library. The deduced 349-residue protein is identical to the bovine protein. Northern blot analysis identified a 3.8-kb mRNA transcript.
Neer et al. (1987) cloned and characterized cDNA encoding the predominant alpha(i) of brain, together with a very similar cDNA that encodes another putative G protein, alpha(h).
By screening human genomic libraries with rat cDNAs for Gi-alpha as probes, Itoh et al. (1988) isolated 3 genes for the alpha subunit. Southern blot analysis indicated that a single copy of each of the 3 genes is present in the haploid human genome.
Blatt et al. (1988) mapped GNAI1 to chromosome 7 by hybridization of cDNA clones with DNA from human-mouse somatic cell hybrids. Bloch et al. (1988) mapped the GNAI1 gene to chromosome 7q21 by in situ hybridization. They confirmed the regional location by studying human/mouse somatic cell hybrid lines containing portions of human chromosome 7.
By the study of restriction fragment length variation (RFLV) in an interspecific backcross between C57BL/6J and Mus spretus mice, Wilkie et al. (1992) demonstrated that the corresponding murine gene is located on chromosome 5.
In a bacterial expression system, Lan et al. (1998) found that point mutations in the Gnai1 and Gnao1 genes, G183S and G184S, respectively, resulted in resistance to regulators of G protein signaling proteins (RGS). The mutant G-alpha proteins showed significantly decreased affinity for RGS4 (602516) and RGS7 (602517).
Ogden et al. (2008) presented in vitro and in vivo evidence in Drosophila that Smoothened (601500) activates G-alpha-i to modulate intracellular cAMP levels in response to hedgehog (see 600725). Ogden et al. (2008) concluded that Smoothened functions as a canonical G protein-coupled receptor, which signals through Gnai1 to regulate hedgehog pathway activation.
In 8 unrelated patients with neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities (NEDHISB; 619854), the Deciphering Developmental Disorders Study (2017) identified de novo heterozygous mutations in the GNAI1 gene (see, e.g., 139310.0001). There were 5 missense mutations and 3 in-frame intragenic deletions. The patients were ascertained from large cohorts of thousands of individuals with developmental delay who underwent exome sequencing. Functional studies of the variants were not performed.
In 24 unrelated patients with NEDHISB, Muir et al. (2021) identified 16 different heterozygous mutations in the GNAI1 gene (see, e.g., 139310.0001-139310.0005). The patients were ascertained through international collaboration after exome sequencing identified the mutations. Thirteen of the patients had previously been reported (see, e.g., Deciphering Developmental Disorders Study, 2017). There were 12 missense mutations, 3 small in-frame deletions, and 1 frameshift mutation; none were present in the gnomAD database. The frameshift mutation was predicted to escape nonsense-mediated mRNA decay as it occurred in the penultimate exon. The mutations occurred de novo in all except 1 patient who inherited it from an unaffected mosaic mother. Although functional studies of the variants were not performed, structural modeling predicted that most would affect guanine nucleotide (GDP and GTP) binding motifs in GAI1 and disrupt proper GAI1 function. There were no obvious genotype/phenotype correlations.
In a pair of monozygotic twin boys with NEDHISB, Wayhelova et al. (2022) identified a de novo heterozygous missense mutation in the GNAI1 gene (D272G; 139310.0006). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; it was classified as pathogenic according to ACMG criteria. Functional studies of the variant were not performed. The authors noted that the GNAI1 gene is expressed in multiple fetal and postnatal brain structures and that disruption of gene function may lead to impaired neural development.
In a female patient (268385) with neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities (NEDHISB; 619854), the Deciphering Developmental Disorders study (2017) identified a de novo heterozygous c.995T-A transversion (c.995T-A, ENST00000351004) in the GNAI1 gene, resulting in a val332-to-glu (V332E) substitution. The patient was ascertained from a large cohort of thousands of individuals with developmental delay who underwent exome sequencing. Functional studies of the variant were not performed. This same patient was reported by Muir et al. (2021) as an 18-year-old woman (P24) who was nonverbal and nonambulatory with severe-to-profound intellectual disability, hypertonia, and obesity.
In 2 unrelated patients (P3 and P4) with neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities (NEDHISB; 619854), Muir et al. (2021) identified a de novo heterozygous c.118G-T transversion (c.118G-T, NM_002069.5) in the GNAI1 gene, resulting in a gly40-to-cys (G40C) substitution in the GDP-binding domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. The mutation occurred de novo in P4 and was inherited from a mother who was mosaic (6%) in P3. Both patients had early-onset seizures and were essentially nonverbal. P3 had autistic features and P4 was nonambulatory with spastic tetraparesis at age 11 years. Functional studies of the variant were not performed.
In 3 unrelated patients (P6, P7, and P8) with neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities (NEDHISB; 619854), Muir et al. (2021) identified a de novo heterozygous c.143C-A transversion (c.143C-A, NM_002069.5) in the GNAI1 gene, resulting in a thr48-to-lys (T48K) substitution in the GDP-binding domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed. The patients had global developmental delay with delayed or absent speech; 2 were noted to have profound intellectual disability. All had hypotonia and various types of seizures, including intractable seizures necessitating temporal lobectomy in P8. Brain imaging was abnormal in the 2 patients studied, showing global atrophy and delayed myelination.
In 2 unrelated girls (P17 and P18) with neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities (NEDHISB; 619854), Muir et al. (2021) identified a de novo heterozygous c.671G-A transition (c.671G-A, NM_002069.5) in the GNAI1 gene, resulting in a cys224-to-tyr (C224Y) substitution. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed. P17 was an 11.5-year-old girl with global developmental delay, poor speech, moderate-to-severe intellectual disability, poor eye contact, autistic features, hypotonia, and early-onset hypomotor generalized epilepsy that resolved by age 4 years. P18 was 12-year-old girl with moderate intellectual disability and autism who could speak well and attend a special school. She had hypotonia and dysmorphic features; she did not have seizures. Brain imaging was normal in both patients.
In 2 unrelated patients (P19 and P20) with neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities (NEDHISB; 619854), Muir et al. (2021) identified a de novo heterozygous c.809A-G transition (c.809A-G, NM_002069.5) in the GNAI1 gene, resulting in a lys270-to-arg (K270R) substitution in the GDP-binding domain. The mutation, which was found by exome sequencing, was not present in the gnomAD database. Functional studies of the variant were not performed. The patients had early-onset seizures, hypotonia, and dysmorphic facial features. Brain imaging was normal.
In a pair of monozygotic twin boys with neurodevelopmental disorder with hypotonia, impaired speech, and behavioral abnormalities (NEDHISB; 619854), Wayhelova et al. (2022) identified a de novo heterozygous c.815A-G transition (c.815A-G, NM_002069.6) at the distal part of exon 7 of the GNAI1 gene, resulting in an asp272-to-gly (D272G) substitution at a highly conserved guanine nucleotide binding site. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; it was classified as pathogenic according to ACMG criteria. Functional studies of the variant were not performed. The patients had global developmental delay with severe speech impairment and clumsy motor skills. Seizures were not reported and brain imaging was normal. Twin B developed acute lymphoblastic leukemia that was treated with chemotherapy. Genetic analysis also identified a heterozygous 5-bp deletion in the ATM gene (607585) in both boys that was inherited from their father. The ATM variant (rs1555092477) was classified as pathogenic and may have contributed to the development of acute lymphoblastic leukemia in twin B. Microarray analysis identified a familial heterozygous 8q24.23-q24.3 duplication and a heterozygous 5q13.2 deletion that were not thought to contribute to the neurodevelopmental phenotype.
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Bloch, D. B., Bloch, K. D., Iannuzzi, M., Collins, F. S., Neer, E. J., Seidman, J. G., Morton, C. C. The gene for the alpha-i-1 subunit of human guanine nucleotide binding protein maps near the cystic fibrosis locus. Am. J. Hum. Genet. 42: 884-888, 1988. [PubMed: 3130752]
Bray, P., Carter, A., Guo, V., Puckett, C., Kamholz, J., Spiegel, A., Nirenberg, M. Human cDNA clones for an alpha subunit of G(i) signal-transduction protein. Proc. Nat. Acad. Sci. 84: 5115-5119, 1987. [PubMed: 3110783] [Full Text: https://doi.org/10.1073/pnas.84.15.5115]
Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature 542: 433-438, 2017. [PubMed: 28135719] [Full Text: https://doi.org/10.1038/nature21062]
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Lan, K.-L., Sarvazyan, N. A., Taussig, R., Mackenzie, R. G., DiBello, P. R., Dohlman, H. G., Neubig, R. R. A point mutation in G-alpha-o and G-alpha-i1 blocks interaction with regulator of G protein signaling proteins. J. Biol. Chem. 273: 12794-12797, 1998. [PubMed: 9582306] [Full Text: https://doi.org/10.1074/jbc.273.21.12794]
Muir, A. M., Gardner, J. F., van Jaarsveld, R. H., de Lange, I. M., van der Smagt, J. J., Wilson, G. N., Dubbs, H., Goldberg, E. M., Zitano, L., Bupp, C., Martinez, J., Srour, M., and 44 others. Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia. Genet. Med. 23: 881-887s, 2021. [PubMed: 33473207] [Full Text: https://doi.org/10.1038/s41436-020-01076-8]
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Wilkie, T. M., Gilbert, D. J., Olsen, A. S., Chen, X.-N., Amatruda, T. T., Korenberg, J. R., Trask, B. J., de Jong, P., Reed, R. R., Simon, M. I., Jenkins, N. A., Copeland, N. G. Evolution of the mammalian G protein alpha subunit multigene family. Nature Genet. 1: 85-91, 1992. [PubMed: 1302014] [Full Text: https://doi.org/10.1038/ng0592-85]