. 2017 Nov 10;34(3):549–565. doi: 10.1007/s12264-017-0191-5

Table 2.

Summary of GRIN2A mutations identified in epilepsy

GRIN2A	Protein (cases)	Gene	Zygosity	Origin	Location	Functional validation	Consequences	Phenotype	References
Deletion (16)	Not known	del chr16: 9 850 000–9 900 000 (hg19)	Het					ABPE	[30]
	Not known	del chr16: 9 825 000–10 075 000 (hg19)	Het					RE + Mild ID	[30]
	Not known	del chr16: 10 250 000–10 275 000 (hg19)	Het					RE	[30]
	Not known	del chr16: 7 964 000–10 607 500 (hg19)						Pseudo-Lennox Syndrome + Severe ID	[31]
	p.Lys592fs (predicted)	del chr16: 8 992 500–9 992 500 (hg19)			M2			RE + Moderate ID	[31]
	Not known	del chr16: 9 365 500–11 273 700 (hg19)						Myoclonic seizures + Severe ID	[31]
	p.Arg865fs (predicted)	del chr16: 9 809 522–9 856 618 (hg19)			CTD			RE + Mild ID	[32]
	p.Phe670fs (4)	del chr16: 9 908 477–9 934 830 (hg19) (2)		Inherited	LBD (S2)			LKS (proband); LKS + VD (two brothers); BCE	[33]
	Not known (3)	del chr16: 10 227 121–10 354 862 (hg19)		Inherited				CSWSS + VD (three brothers)	[33]
	Not known	16p13.2 microdeletion		Inherited				Focal seizures + Delayed cognition	[34]
	Not known	16p13.2p13.13 microduplication		De novo				Epilepsy + ID + Delayed speech	[35]
	p.Pro31Serfs*107 (3)	c.90delTins(T)2	Het	Inherited	ATD			RE (proband, brother, father)	[30]
	p.Phe528Glyfs*22	c.1586delT	Het		LBD (S1)			CSWS + Severe LD	[36]
	p.Val529Trpfs*22 (3)	c.1585delG	Het	Inherited	LBD (S1)			BECTS + Mild ID (proband, brother, father)	[30]
	p.Ser547del	c.1637_1639delCTT	Het		S1-M1 linker			ABPE/CSWS + ID	[30]
	p.Leu779Serfs*5	c.2334_2338delCTTGC	Het	Inherited	LBD (S2)			ABPE/CSWS	[30]
Duplication (3)	Not known	dup chr16: 10 075 000–10 225 000 (hg19)	Het					CSWSS + ID	[30]
	Not known	c.2008-32_c.2008-31dupCT	Het					Epilepsy	[29]
	Not known	Exon 4 & 5	Het					EE	[36]
Translocation (1)	Not known (4)	t (16;17) (p13;q11)		Inherited				FS + GTCS + Severe ID (proband); GTCS + learning difficulties (father, aunt); Seizures + severe ID (cousin)	[29]
Splice-site (4)	Not known	c.414+7C>T		Inherited				IS (Mother unaffected)	[37]
	p.Phe139fs (predicted) (12)	c.1007+1G>A	Het		ATD			LKS + MR	[30]
		c.1007+1G>A	Het	Inherited				ABPE + Delayed cognition	[30]
		c.1007+1G>A	Het	Inherited				BECTS + Delayed cognition	[30]
		c.1007+1G>A	Het	Inherited				CSWSS (proband + father)	[38]
		c.1007+1G>A		Inherited				RE (proband + six relatives)	[38]
		c.1007+1G>T						ABPE/CSWSS	[30]
	p.Val375fs (7)	c.1123–2A>G	Het	Inherited	ATD			CSWSS (proband + brother); CSWSS + dysphasia (aunt); LKS (uncle); RE + dysphasia (grandmother); RE (mother, cousin)	[33]
	Not known (3)	c.2007+1G>A	Het	Inherited				CSWSS (proband); Uncharacterized epilepsy (father)	[30]
		c.2007+1G>A		Inherited				CSWS + Moderate LD (Father unaffected)	[36]
Nonsense (8)	p.Trp198*	c.594G>A	Het		ATD			ABPE + Delayed cognition	[30]
	p.Gln218* (3)	c.652C>T	Het	Inherited	ATD			CTS + moderate ID + MR (proband); FS + focal seizures + learning difficulties (mother); IS + learning difficulties (grandmother)	[29]
	p.Leu334* (3)	c.1001T>A	Het	Inherited	ATD			CSWSS (proband), Panayiotopoulos syndrome (brother), partial epilepsy (father)	[30]
	p.Trp606*	c.1818G>A	Het		M2			ABPE + Mild LD	[36]
	p.Arg681*	c.2041C>T	Het	Inherited	LBD (S2)			LKS + learning disability (proband); learning disability (2)	[30]
	p.Glu803*	c.2407G>T	Het	De novo	S2-M4 linker			LKS + Moderate LD	[36]
	p.Tyr943* (3)	c.2829C>G	Het	Inherited	CTD			CSWSS (proband) + MR; FS + CTS (sister); RE (father)	[30]
	p.Tyr1387* (3)	c.4161C>A		Inherited	CTD			CSWSS + Autistic features (proband); BCE (mother, uncle)	[33]
Missense (50)	p.Met1Thr (3)	c.2T>C		Inherited	ATD			LKS (proband, sister); Seizures + speech/language impairment (father)	[38]
	p.Pro31Thr	c.91C>A			ATD			BECTS	[30]
	p.Pro79Arg (4)	c.236C>G	Het	Inherited	ATD	Glu↓, Gly↓, Total protein↓, Surface expression↓	LOF	CSWSS (proband) + Severe attention deficits; BECTS (mother, uncle, grandmother)	[30, 39]
	p.Thr141Met	c.422C>T	Het		ATD			TLE	[40]
	p.Phe183Ile	c.547T>A	Het	Inherited	ATD			BECTS + Delayed cognition	[30]
	p.Ile184Ser	c.551T>G		Inherited	ATD	Current ↓, Activation time↑, Deactivation time↑, Surface expression↓	LOF	CSWSS	[33, 41]
	p.Cys231Tyr (3)	c.692G>A	Het	Inherited	ATD	Glu↓, Gly↓, Total protein→, Surface expression↓	LOF	LKS + ID (proband); CTS (brother, sister)	[30, 39]
	p.Ala243Val	c.728C>T	Het		ATD	Glu→, Zn²⁺↓	GOF	BECTS + Learning problems	[30]
	p.Ala290Val	c.869C>T	Het		ATD			BECTS	[30]
	p.Gly295Ser	c.883G>Ac			ATD			RE	[33]
	p.Arg370Trp	c.1108C>T	Het		ATD			BECTS	[30]
	p.Cys436Arg	c.1306T>C	Het	De novo	LBD (S1)	Current↓, Glu↑, Gly↓, Total protein↓, Surface expression↓	LOF	ABPE	[30, 39, 42]
	p. Val452Met	c.1354G>A			LBD (S1)	Current→, Glu↑, Gly→, τ_w→, Total protein→, Surface expression→	GOF	Schizophrenia (2)	[42, 43]
		c.1354G>A	Het	De novo	LBD (S1)		GOF	Intractable seizures	[44]
	p.Gly483Arg (2)	c.1447G>A		Inherited	LBD (S1)	Current→, Glu↓, Gly↓, τ_w ↓, Total protein↓, Surface expression↓	LOF	CSWSS + dysphasia (proband); RE + dysphasia (sister)	[33, 39, 42]
	p.Arg504Trp (3)	c.1510C>T		Inherited	LBD (S1)	Current→, Glu→, Gly→, τ_w↑, Total protein↓, Surface expression↓	LOF	CSWSS (proband, father); FS	[33, 42]
	p.Val506Ala			Inherited	LBD (S1)	Current→, Glu↑, Gly→, τ_w→, Total protein→, Surface expression↑	LOF	Focal seizures	[34, 42]
	p.Arg518His (4)	c.1553G>A		Inherited	LBD (S1)	Current↓, activation time↑, deactivation time↑, Surface expression↓, Single-channel open time↑, close time ↓	LOF	CSWSS (proband); RE (brother); VD (father); CTS	[33, 41, 42]
		c.1553G>A			LBD (S1)		LOF	LKS	[45]
	p.Thr531Met (4)	c.1592C>T		Inherited	LBD (S1)	Current↓, Single-channel open time↑	LOF	CSWSS (proband); Epilepsy-aphasia (two brothers); Learning difficulties + speech/language impairment (mother)	[42, 46]
	p.Ala548Thr	c.1642G>A		De novo	S1-M1 linker	Current↓, Glu ↓, Gly ↓, Total protein→, Surface expression→	LOF	LKS	[26, 33]
	p.Pro552Arg	c.1655C>G			S1-M1 linker	Current→, Glu↑, Gly↑, τ_w↑, Total protein→, Surface expression→	GOF	Early-onset seizures + Severe ID + No speech	[26, 47]
	p.Arg586Lys (2)	c.1757G>A	Het	Inherited	M1-M2 linker		No change	Severe EE (parents unaffected)	[29]
		c.1757G>A	Het	Inherited				IS (father unaffected)	[37]
		c.1757G>A				Current→, Mg²⁺→, Ifenprodil→, Single-channel conductance→, open time→		ID	[48]
	p.Asn614Ser	c.1841A>G	Het	De novo	M2			Focal epilepsy + Severe LD	[36]
	p.Asn615Lys	c.1845C>A	Het	De novo	M2	Mg²⁺↓	GOF	EOEE + Severe MR	[29, 49]
	p.Thr646Ala	c.1936A>G	Het	De novo	M3			EE	[36]
	p.Leu649Val	c.1945C>G			M3			Epileptic seizures + Severe ID	[47]
	p.Phe652Val	c.1954T>G		De novo	M3	Single-channel open time↑, close time↓	GOF	CSWSS + Autistic features	[33]
Missense (50)	p.Lys669Asn	c.2007G>T		De novo	LBD (S2)	Current→, Glu↑, Gly↑, τ_w↑, Total protein→, Surface expression→	GOF	CSWSS	[33, 42]
	p.Val685Gly	c.2054T>G			LBD (S2)	Current↓, Glu↓, Gly→, τ_w↓, Total protein↓, Surface expression↓	LOF	Severe intractable epilepsy+ DD	[42]
	p.Ile694Thr	c.2081T>C		De novo	LBD (S2)	Current↓, Glu↓, Gly→, τ_w→, Total protein↓, Surface expression↓	LOF	LKS	[33, 42]
	p.Pro699Ser	c.2095C>T	Het	De novo	LBD (S2)	Current→, Glu↑, Gly→, τ_w→, Total protein→, Surface expression↓	GOF	BECTS	[30, 42]
	p.Met705Val	c.2113A>G	Het	Inherited	LBD (S2)	Current→, Glu↓, Gly→, τ_w→, Total protein→, Surface expression↓	LOF	BECTS	[30, 39, 42]
	p.Glu714Lys	c.2140G>A	Het		LBD (S2)	Current→, Glu→, Gly→, τ_w→, Total protein↓, Surface expression↓	LOF	CSWSS	[30, 39, 42]
	p.Ala716Thr (8)	c.2146G>A		Inherited	LBD (S2)	Current→, Glu↓, Gly→, τ_w ↓, Total protein↓, Surface expression↓	LOF	RE + VD (proband + six relatives); VD (cousin)	[33, 41, 42]
		c.2146G>A	Het		LBD (S2)		LOF	LKS +LD + Diffuse hypotonia + Lack of motor coordination.	[50]
	p.Ala727Thr	c.2179G>A	Het		LBD (S2)	Current→, Glu↓, Gly→, τ_w→, Total protein↓, Surface expression↓	LOF	BECTS	[30, 42]
	p.Asp731Asn (3)	c.2191G>A	Het	De novo	LBD (S2)	Glu↓, H⁺↑,Zn²⁺↑,τ_w↓ , P0↓	LOF	Unexplained epilepsy + DD	[42, 51]
		c.2191G>A		De novo				LKS	[52]
		c.2191G>A		Inherited		Current↓, Glu↓, Gly↓, Total protein↓, Surface expression↓		RE + VD (proband); VD (mother)	[33, 39, 42]
	p.Val734Leu (2)	c.2200G>C	Het	Inherited	LBD (S2)	Current→, Glu↓, Gly→, τ_w↓, Total protein→, Surface expression→	LOF	BECTS (proband, brother)	[30, 42]
	p.Lys772Glu	c.2314A>G	Het		LBD (S2)	Current→, Glu↓, Gly→, τ_w→, Total protein↓, Surface expression↓	LOF	ABPE + Learning and reading problems	[30, 42]
	p.Leu812Met	c.2434C>A	Het	De novo	S2-M4 linker	Current→, Glu↑, Gly↑, Mg²⁺↓, H⁺↓,Zn²⁺↓, τ_w↓, P₀↑	GOF	EOEE + DD	[72]
	p.Ile814Thr	c.2441T>C	Het	Inherited	S2-M4 linker	Glu→, Gly→, Total protein→, Surface expression→	No change	BECTS	[30, 39]
	p.Met817Val (2)	c.2449A>G		De novo	M4	Current→, Glu↑, Gly↑, Mg²⁺↓, H⁺↓, Zn²⁺↓, τ_w↓, P0↑	GOF	Refractory epilepsy + DD	[53, 54]
		c.2448C>T		De novo	M4		GOF	Unexplained epilepsy + ID	[52]
	p.Ile876Thr	c.2627T>C	Het		CTD			TLE	[40]
	p.Ile904Phe (3)	c.2710A>T	Het	Inherited	CTD			BECTS + Delayed cognition (proband, father); FS + CTS (brother)	[30]
	p.Asp933Asn	c.2797G>A		Inherited	CTD	Glu→, Gly→, Total protein→, Surface expression→	No change	LKS	[33, 39]
	p.Val967Leu (12)	c.2899G>C	Het		CTD			TLE	[40]
		c.2899G>C			CTD			ABPE (2); ABPE/unclassified epilepsy; BECTS (8)	[30]
	p.Asn976Ser	c.2927A>G	Het		CTD	Glu→, Gly→, Total protein→, Surface expression→	No change	ABPE/CSWS	[30, 39]
Missense (50)	p.Thr1064Ala (2)	c.3190A>G			CTD			Schizophrenia	[43]
		c.3190A>G	Het	Inherited				Epilepsy	[29]
		c.3190A>G	Het					BECTS	[30]
	p.Asn1076Lys (3)	c.3228C>G	Het		CTD			BECTS	[29, 30]
		c.3228C>G		Inherited				BECTS	[29, 30]
		c.3228C>G		Inherited				LKS	[29, 30]
	p.Asp1251Asn (2)	c.3751G>A		Inherited	CTD			RE (proband); Absence epilepsy (father)	[33]
	p.Ala1276Gly (3)	c.3827C>G			CTD			CSWSS (2); BECTS	[30, 33]
	p.Ile1379Val	c.4135A>G		De novo	CTD			Juvenile Absence Epilepsy	[40]

ATD amino-terminal domain, ABPE atypical benign partial epilepsy, BCE benign childhood epilepsy, BECTS benign epilepsy with centro-temporal spikes, CSWS continuous spike and slow-wave during sleep, CTS centro-temporalspikes, DD developmental delay, FS febrile seizures, GOF gain-of-function, GTCS generalized tonic-clonic seizures, IS infantile spasms, LD language delay, LKS Landau-Kleffner syndrome, MR mental retardation, P ₀ single-channel open probability, RE Rolandic Epilepsy, TLE temporal lobe epilepsy, VD verbal dyspraxia, τ _w deactivation time course

↑ increase