Alternative titles; symbols
HGNC Approved Gene Symbol: GAD1
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38): 2:170,813,210-170,861,151 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q31.1 | Developmental and epileptic encephalopathy 89 | 619124 | Autosomal recessive | 3 |
The GAD1 gene encodes glutamate decarboxylase-67 (GAD67) (L-glutamate-1-carboxylyase; EC 4.1.1.15), an enzyme that catalyzes the conversion of glutamic acid to gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the vertebral central nervous system. GAD67 is the major isoform at embryonic stages and plays an essential role in neuronal development and synaptogenesis (summary by Chatron et al., 2020)
See also GAD2 (138275), which encodes GAD65 and maps to chromosome 10p11.23.
Erlander et al. (1991) determined that the brain contains 2 forms of GAD which differ in molecular size, amino acid sequence, antigenicity, cellular and subcellular location, and interaction with the GAD cofactor pyridoxal phosphate (PLP). They reported the cloning of rat Gad65 and demonstrated the different nucleotide sequences of rat Gad65 and Gad67. The 2 cDNAs hybridized to genomic fragments of different sizes, implying that they are encoded by 2 distinct genes. Erlander et al. (1991) showed that the enzymatic activity of Gad65 was more responsive to PLP than that of Gad67.
Kelly et al. (1992) isolated a cDNA corresponding to the GAD67 gene from a human frontal cortex cDNA library. Bu et al. (1992) isolated a GAD1 cDNA clone from a human fetal brain cDNA library. The deduced 594-amino acid protein has a molecular mass of 67 kD. The protein showed 97% and 98% identity to the rat and feline proteins, respectively. The human GAD65 and GAD67 proteins showed 65% identity. Northern blot analysis detected a 3.7-kb mRNA transcript for GAD67.
Xiang et al. (2007) reported that an excitatory rather than inhibitory GABAergic system exists in airway epithelial cells. Both GABA-A receptors and the GABA synthetic enzyme glutamic acid decarboxylase are expressed in pulmonary epithelial cells. Activation of GABA-A receptors depolarized these cells. The expression of GAD in the cytosol and GABA-A receptors in the apical membranes of airway epithelial cells increased markedly when mice were sensitized and then challenged with ovalbumin, an approach for inducing allergic asthmatic reactions. Similarly, GAD and GABA-A receptors in airway epithelial cells of humans with asthma increased after allergen inhalation challenge. Intranasal application of selective GABA-A receptor inhibitors suppressed the hyperplasia of goblet cells and the overproduction of mucus induced by ovalbumin or interleukin-13 (147683) in mice. Xiang et al. (2007) concluded that the airway epithelial GABAergic system has an essential role in asthma.
Donato et al. (2013) showed that environmental enrichment and Pavlovian contextual fear conditioning induce opposite, sustained, and reversible hippocampal parvalbumim (PV; 168890) network configurations in adult mice. Specifically, enrichment promotes the emergence of large fractions of low differentiation (low PV and GAD67 expression) basket cells with low excitatory-to-inhibitory synaptic density ratios, whereas fear conditioning leads to large fractions of high differentiation (high PV and GAD67 expression) basket cells with high excitatory-to-inhibitory synaptic density ratios. Pharmacogenetic inhibition or activation of PV neurons was sufficient to induce such opposite low-PV-network or high-PV-network configurations, respectively. The low-PV-network configuration enhanced structural synaptic plasticity, and memory consolidation and retrieval, whereas these were reduced by the high-PV-network configuration. Donato et al. (2013) then showed that maze navigation learning induces a hippocampal low-PV-network configuration paralleled by enhanced memory and structural synaptic plasticity throughout training, followed by a shift to a high-PV-network after learning completion. The shift to a low-PV-network configuration specifically involved increased vasoactive intestinal peptide (VIP; 192320)-positive GABAergic boutons and synaptic transmission onto PV neurons. Closely comparable low- and high-PV-network configurations involving VIP boutons were specifically induced in primary motor cortex upon rotarod motor learning. Donato et al. (2013) concluded that their results uncovered a network plasticity mechanism induced after learning through VIP-PV microcircuit modulation, and involving large, sustained, and reversible shifts in the configuration of PV basket cell networks in the adult.
Bu and Tobin (1994) determined that the GAD1 gene contains 16 exons spanning approximately 45 kb of genomic DNA. The GAD2 gene also contains 16 exons, but spans more than 79 kb. GAD2 exon 1 contains the 5-prime untranslated region of the mRNA, and exon 16 specifies the protein's C terminus and at least part of the mRNA's 3-prime untranslated sequence. The GAD1 gene contains an additional exon (exon 0) that, together with part of exon 1, specifies the 5-prime untranslated region of GAD1 mRNA. Exon 16 specifies the entire 3-prime untranslated region of GAD1 mRNA. Exons 1-3 encode the most divergent region of the 2 genes. The remaining exon-intron boundaries occur at identical positions in the 2 cDNAs, suggesting that the 2 genes derived from a common ancestral GAD gene.
By somatic cell hybridization, Sparkes et al. (1987) assigned the GAD gene to chromosome 2.
Kelly et al. (1992) confirmed the assignment of GAD1 to chromosome 2 by using PCR to amplify specifically the human sequence in rodent/human somatic cell hybrid DNAs. By FISH, Bu et al. (1992) mapped the GAD1 gene to 2q31.
Brilliant et al. (1990) showed by Southern analysis of mouse-hamster hybrid cells and by interspecific backcrosses and recombinant inbred strains that the mouse Gad1 gene is located on chromosome 2 and that an apparent pseudogene is located on mouse chromosome 10.
By in situ hybridization, Edelhoff et al. (1993) assigned GAD1 to human 2q31 and to mouse chromosome 2D in a known region of conservation between human and mouse.
Developmental and Epileptic Encephalopathy 89
In 11 patients from 5 unrelated consanguineous families of various ethnic origins with developmental and epileptic encephalopathy-89 (DEE89; 619124), Chatron et al. (2020) identified homozygous mutations in the GAD1 gene (605363.0002-605363.0006). The patients were ascertained through the GeneMatcher program after whole-exome or whole-genome sequencing identified biallelic GAD1 mutations. The mutations, which were confirmed by Sanger sequencing, segregated with the disorder in the families. There were 2 nonsense, 1 frameshift, 1 splice site, 1 in-frame deletion, and 1 missense mutation. Studies of the splice site and in-frame deletion showed that the former altered splicing and the latter was expressed at normal levels. Additional functional studies of the variants and studies of patient cells were not performed, but all the variants were predicted to result in a loss of function. Chatron et al. (2020) noted that since the GAD1 gene is involved in inhibitory synaptic transmission in the nervous system, a loss of function could lead to excessive excitatory drive on motor neurons, resulting in seizures and hypertonia, which was observed in the patients.
In 6 unrelated patients of different ethnicities with DEE89, Neuray et al. (2020) identified biallelic mutations in the GAD1 gene (see, e.g., 605373.0005 and 605363.0007-605363.0009). The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype in all families except one in which the father was not sequenced. Functional studies were not performed.
In a patient with DEE89, von Hardenberg et al. (2020) identified a homozygous splicing mutation in the GAD1 gene (605363.0010), resulting in skipping of exon 11. The deletion affects the pyridoxal-dependent decarboxylase domain of GAD1, including deletion of an active site residue (tyr347) and a functional residue (asp373) involved in pyridoxal 5-prime phosphate binding.
Associations Pending Confirmation
Because of the finding of cleft palate in Gad67 knockout mice (Asada et al., 1997; Condie et al., 1997), Kanno et al. (2004) investigated the possible association between the GAD67 gene and nonsyndromic cleft lip with or without cleft palate (119530) in Japanese patients. They screened 50 probands for SNPs in GAD67 using denaturing high performance liquid chromatography (DHPLC) and found 7 SNPs. Five were used to construct a haplotype of GAD67. The frequency distribution of the haplotype differed between patients with nonsyndromic cleft lip with or without cleft palate and controls. A transmission disequilibrium test in 99 parent-offspring trios suggested that 1 haplotype was preferentially transmitted to the patients with cleft lip and palate (P = 0.0077).
In addition to its role as an inhibitory neurotransmitter, GABA is presumed to be involved in the development and plasticity of the nervous system. Asada et al. (1997) found that Gad67 -/- mice were born at the expected frequency but died of severe cleft palate during the first morning after birth. GAD activities and GABA contents were reduced to 20% and 7%, respectively, in the cerebral cortex of the newborn Gad67 -/- mice. Their brains, however, did not show any discernible defects. Previous pharmacologic and genetic investigations suggested the involvement of GABA in palate formation, but this was the first demonstration of a role for GAD67-derived GABA in the development of nonneural tissue.
Independently, Condie et al. (1997) found defects in the formation of the palate in mice with a targeted mutation in the gene encoding Gad67. Previous observations had suggested a role of GABA in palate development. Analysis of mice with mutations in the beta-3 gamma-GABA receptor (GABRB3; 137192) had demonstrated that these mutations are associated with cleft secondary palate in mice. The phenotype in the GABRB3 mutants showed that this gene is somehow involved in palate development but did not demonstrate that GABA is the ligand involved in this particular function. The results of Condie et al. (1997), demonstrating a similar phenotype between the receptor and ligand mutations, demonstrated a role for GABA signaling in normal palate development.
Yoon et al. (1999) made transgenic mice expressing an antisense construct against GAD65 and GAD67. The various lines of mice expressed different amounts of the antisense GAD. Beta cell-specific suppression of GAD expression in 2 lines of antisense GAD transgenic NOD (nonobese diabetic) mice prevented autoimmune diabetes, whereas persistent GAD expression in the beta cells in the other 4 lines of antisense GAD-transgenic NOD mice resulted in diabetes similar to that seen in transgene-negative NOD mice. Complete suppression of beta-cell GAD expression blocked the generation of diabetogenic T cells and protected islet grafts from autoimmune injury. Thus, beta cell-specific GAD expression is required for the development of autoimmune diabetes in NOD mice, and modulation of GAD might, therefore, have therapeutic value in type I diabetes (222100). The expression of GAD was blocked only in beta islet cells and not in brain. In addition to the absence of T cells directed against GAD, there were also fewer T cells reactive to other beta islet-specific autoantigens, such as insulin, in the antisense NOD mice, but not in nontransgenic control animals. In an accompanying article, von Boehmer and Sarukhan (1999) suggested that GAD is the initiating autoantigen in human type I diabetes because GAD-specific autoantibodies are among the first to appear in the prediabetic phase in human patients.
Abuse of the dissociative anesthetic ketamine can lead to a syndrome indistinguishable from schizophrenia. In animals, repetitive exposure to this N-methyl-D-aspartate receptor antagonist induced the dysfunction of a subset of cortical fast-spiking inhibitory interneurons, with loss of expression of parvalbumin (168890) and the gamma-aminobutyric acid-producing enzyme GAD67. Behrens et al. (2007) showed that exposure of mice to ketamine induced a persistent increase in brain superoxide due to activation in neurons of reduced NADPH oxidase (300225). Decreasing superoxide production prevented the effects of ketamine on inhibitory interneurons in the prefrontal cortex. Behrens et al. (2007) concluded that their results suggested that NADPH oxidase may represent a novel target for the treatment of ketamine-induced psychosis.
Edelhoff et al. (1993) reported the mapping of 'a potential GAD3 transcript' to chromosome 22q13. Lernmark (1994) later retracted this assignment.
This variant, formerly titled CEREBRAL PALSY, SPASTIC QUADRIPLEGIC, 1, based on the report of Lynex et al. (2004), has been reclassified based on a report by Morgan et al. (2021).
In 4 affected sibs of a consanguineous Pakistani family with autosomal recessive spastic quadriplegic cerebral palsy (CPSQ1) reported by Mitchell and Bundey (1997), Lynex et al. (2004) identified a homozygous 36G-C transversion in exon 1 of the GAD1 gene, resulting in a ser12-to-cys (S12C) substitution in the N-terminal domain. The variant was not identified in 200 control chromosomes. Functional studies of the variant were not performed. The patients did not have seizures.
In the family reported by Lynex et al. (2004), Morgan et al. (2021) identified a pathogenic mutation in the HPDL gene (L176P; 618994.0007) that segregated with the disorder, now designated neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA; 619026). Morgan et al. (2021) noted that the GAD1 S12C mutation did not segregate with the disorder in the family.
In 2 sibs, born of consanguineous parents of Algerian descent (family A), with developmental and epileptic encephalopathy-89 (DEE89; 619124), Chatron et al. (2020) identified a homozygous G-to-C transversion in intron 14 of the GAD1 gene (c.1414-1G-C, NM_000817.2), resulting in a splice site alteration. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Analysis of patient cells confirmed that it caused splicing defects with absence of the normal transcript and the presence of 3 aberrant isoforms. Additional functional studies of the variant were not performed, but the variant was predicted to result in a loss of function. The patients had onset of seizures in the first days or months of life; EEG showed hypsarrhythmia. Although both patients showed a good seizure response to vigabatrin treatment, they had severely impaired global development with spastic paresis and inability to sit or speak.
In 2 sibs, born of consanguineous parents of Egyptian descent (family B), with developmental and epileptic encephalopathy-89 (DEE89; 619124), Chatron et al. (2020) identified a homozygous 3-bp in-frame deletion (c.695_697delAGA, NM_000817.2) in exon 7 of the GAD1 gene, resulting in the deletion of conserved residue lys231 (Lys231del). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in public databases, including gnomAD. It was predicted to alter a splice site, resulting in a frameshift and premature termination. However, in vitro studies in E. coli transfected with the mutation showed expression of the variant protein at the same levels as wildtype. Additional functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function. The patients had onset of seizures at 2 weeks of age. Although both patients showed a good seizure response to vigabatrin treatment, they had severely impaired global development with spastic paresis and inability to sit or speak. Both died, at 2 and 4 years of age.
In 2 sibs, born of consanguineous parents of Turkish descent (family C), with developmental and epileptic encephalopathy-89 (DEE89; 619124), Chatron et al. (2020), identified a homozygous 5-bp deletion (c.812_816delTTAAG, NM_000817.2), resulting in a frameshift and premature termination (Val271AspfsTer9). The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function. The patients had onset of refractory myoclonic seizures at 2 weeks and day 1 of life. EEG showed a burst-suppression pattern. One sib died at 2 years of age.
In 4 patients from 2 unrelated consanguineous families of Iranian and Turkish descent (families D and E) with developmental and epileptic encephalopathy-89 (DEE89; 619124), Chatron et al. (2020) identified a homozygous c.1591C-T transition (c.1591C-T, NM_000817.2) in exon 17 of the GAD1 gene, resulting in an arg531-to-ter (R531X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The mutation was present at a low level in the heterozygous state in the gnomAD database (3.98 x 10(-6)). Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function. The authors postulated that these patients may share a haplotype. The patients had onset of seizures in the first days or weeks of life. EEG showed hypsarrhythmia or a burst-suppression pattern.
In an African American male (family C) with DEE89, Neuray et al. (2020) identified compound heterozygous mutations in the GAD1 gene: R531X and a 1-bp deletion (c.670delC; 605363.0008) predicted to result in a frameshift and premature termination (Leu224SerfsTer5). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing; the mother was shown to be a mutation carrier but the father was not tested. The c.670delC mutation was not present in the gnomAD database. Both mutations were predicted to result in a truncated protein or nonsense-mediated decay.
In a 7-year-old girl, born of consanguineous parents of Brazilian descent (family F), with developmental and epileptic encephalopathy-89 (DEE89; 619124), Chatron et al. (2020) identified a homozygous c.1525G-A transition (c.1525G-A, NM_000817.2) in the GAD1 gene, resulting in a glu509-to-lys (E509K) substitution at a conserved residue. The mutation, which was found by whole-exome exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function. The patient had onset of seizures in the first week of life. EEG showed multifocal discharges and a burst-suppression pattern. Although treatment with vigabatrin resulted in seizure control, she had severe global developmental delay and was unable to sit or speak.
In a girl, born of consanguineous parents of Persian descent (family A), with developmental and epileptic encephalopathy-89 (DEE89; 619124), Neuray et al. (2020) identified a homozygous c.1691A-G transition (c.1691A-G, NM_013445.3) in the GAD1 gene, resulting in an asn564-to-ser (D564S) substitution. The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents. The mutation was present in the gnomAD database with a heterozygote frequency of 0.00000398. The mutation is located in the C-terminal domain and was predicted to result in partial loss of function of catalytic activity. The patient had moderately impaired intellectual development, mild hypotonia, developmental delay, and epilepsy, which presented at 2 months of age.
For discussion of the 1-bp deletion (c.670delC, NM_013445.3) in the GAD1 gene, predicted to result in a frameshift and premature termination (Leu224SerfsTer5), that was found in compound heterozygous state in a patient (family C) with developmental and epileptic encephalopathy-89 (DEE89; 619124) by Neuray et al. (2020), see 605363.0005.
In a girl, born of consanguineous parents of Egyptian descent (family E), with developmental and epileptic encephalopathy-89 (DEE89; 619124), Neuray et al. (2020) identified homozygosity for a c.87C-G transversion (c.87C-G, NM_013445.3) in the GAD1 gene, resulting in a tyr29-to-ter (Y29X) substitution. The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents and was not present in the gnomAD database. The mutation, which is located in the N-terminal domain, was predicted to result in nonsense-mediated decay. The patient had severely impaired intellectual development, hypotonia, hearing loss, developmental delay, and epilepsy, which presented at 6 months of age.
In a female infant, born to nonconsanguineous German parents, with developmental and epileptic encephalopathy-89 (DEE89; 619124), von Hardenberg et al. (2020) identified a homozygous c.1119+1G-A splice site mutation (c.1119+1G-A, NM_000817.2) in intron 10 of the GAD1 gene, resulting in skipping of exon 11 and leading to an in-frame deletion of 39 amino acids (Gly335_Asp373del). The mutation was identified by trio whole-exome sequencing, and exon 11 skipping was confirmed by sequencing of cDNA from the patient. The deletion affects the pyridoxal-dependent decarboxylase domain of GAD1. Functional studies were not performed.
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