Table 2.

Features of mutations in Cx43 associated with ODDD

Mutation	Functional assay (transfected cell lines unless noted)	Localization in mammalian cells (transfected cell lines unless noted)	Neurologic phenotype	References
Explicit statement of no neurologic manifestations
S5C			9 YO “no mental retardation or brain wave abnormality.” [201]	[201]
L11P			13 YO, de novo mutation.	[202]
			No neuro. findings. [202]
S18P		GJ-like plaques. (S. Scherer, unpublished)	No neuro. findings. [152]	[152] originally described in [203, 204];
V41A			11 YO, neuro. exam nl.	[205]
Q49K	Low homotypic coupling and minimal dominant negative effect on endogenous Cx43 mediated NRK cell coupling. [185]	GJ-like plaques. [185] (S. Scherer, unpublished)	No neuro. findings. [152]	[152] originally described in [206];
F52dup	No junctional homotypic coupling. [189]	ER staining pattern [189] Very reduced puncta. [188] Normal localization (basolateral) in MDCK cells. [186]	No neuro. findings. [152]	[152] originally described in [207];
	No dye transfer by scrape load or hemichannel activity by dye uptake. [188]	Endosomal. (S. Scherer, unpublished)
P59H			No neuro. findings.	[208]
R76H			Affected child has homozygous mutation; parents are heterozygotes; no neuro. findings.	[209].
V96E			12 YO with de novo mutation in; no neuro. findings.	[157]
Y98C		GJ-like plaques. (S. Scherer, unpublished)	No neuro. findings. [152]	[152] originally described in [206, 210];
H194P	Normal hemichannel activity. No neurobiotin transfer [193]	GJ-like plaques and cytopasmic. [187]	No syndactyly or spastic paraplegia. [156, 211]	[211]
R202H	No homotypic coupling. [189]	GJ-like plaques (S. Scherer, unpublished)	No neuro. findings. [152]	[152, 212, 213]
	Low coupling and dominant negative effect on endogenous Cx43 mediated NRK coupling. [185]	No plaques, some overlap with ER marker. [189]
		Few plaques partial intracellular retention. [185]
C260fs	Decreased endogenous plaques when expressed in NRK cells; decreased coupling and dominant negative effect on WT Cx43 in transfected cells [192]	ER retained [192]	Neurologically normal [214]	[214]
Y230fs			No neuro. or eye problems. [156, 215]	[215]
A253V			Polymorphism	[152]
Neurologic manifestations not mentioned
G2V			Nothing stated.	[216]
L7V			Nothing stated.	[156]
G22R			Nothing stated.	[156]
S27P			Nothing stated.	[212]
I31M			Nothing stated.	[212]
E48K			Nothing stated.	[217]
				[218]
Q49dup			Nothing stated.	[156]
N55D			Nothing stated.	[156]
Q58H			Nothing stated.	[156]
P59A			Nothing stated.	[156]
P59H			Nothing stated.	[219]
S69Y			Nothing stated.	[212]
H74L			Nothing stated.	[156]
V85M			Nothing stated.	[213]
V96M			Nothing stated.	[220]
E110D			Nothing stated.	[221]
I131M	Increased hemichannel activity.	GJ-like plaques and cytopasmic. [187]	Nothing stated.	[212]
	No neurobiotin transfer.[187]
G138D			Nothing stated.	[213]
G138S			Nothing stated.	[156, 213]
G143S	Increased hemichannel activity.	GJ-like plaques and cytopasmic. [187]	Nothing stated.	[212]
	No neurobiotin transfer. [193]
G143D			Nothing stated.	[213] [156]
K144E			Nothing stated.	[156]
V145G			Nothing stated.	[156]
M147T			Sporadic case; nothing stated.	[221]
R148Q			Nothing stated.	[212] originslly described in [222]
R148G			Nothing stated.	[156]
F169del			Nothing stated.	[221]
P193L			Nothing stated.	[156]
S201F			Nothing stated.	[156]
S201Y			Nothing stated.	[213]
Explicit description of neurologic manifestations
G2fs			G2fs+R101x; severe CNS phenotype, psychomotor regression onset age 10, seizures; massive calcifications, hypomyelination, and atrophy on CT/MRI. [173]	[173]
D3N	Decreased coupling in patient fibroblasts. [169]	Partial localiztion in Golgi (but also some WT in golgi distribution) in patient fibroblasts. [169]	Neurogenic bladder, UMN. [169]	[156, 213] [169]
Y17S	No junctional coupling. [189]	GJ-like plaques. (reduced nos.) [188]	“Neuro. deficits were prominent.” [206] UMN, ur. inc. [156]	[152] originally described in [206, 223]
	No dye transfer by scrape load or hemichnnel activity by dye uptake. [188]	GJ-like plaques. (S. Scherer, unpublished)
G21R	No homotypic junctional coupling. [189] [190] No dye transfer by scrape load or hemichnnel activity by dye uptake. [188]	GJ-like plaques. (reduced numbers) [189] [188, 190]	No neuro. symptoms but patient is a 2 YO with a sporadic mutation. [152] UMN. [156]	[152]
	Dominant negative effect on endogenous 43 in NRK cells [190] and Hela and N2a cells. [224]
G22E		GJ-like plaques. (S. Scherer, unpublished)	“Neuro. Symptoms.” [152]	[152] originally described in [225]
K23T		GJ-like plaques. (S. Scherer, unpublished)	“Neuro. Symptoms.” [152] UMN, MRI WMC, tremor. [156]	[152] originally described in [155]
R33x			2 siblings homozygous for this mutation; speech delay, UMN, grossly abnormal grey/white matter differentiation on head CT. [180]	[180, 181]
A40V	No homotypic coupling. [189]	GJ-like plaques. (reduced numbers) [188, 189]	No neuro. symptoms but patient is a 2 YO with a sporadic mutation. [152] gait difficulty, ur. urgency [156]	[152, 212, 221]
	No dye transfer by scrape load or hemichnnel activity by dye uptake.[188]	GJ-like plaques. (S. Scherer, unpublished)
Q49P			Ur. inc.	[156]
R76S		GJ-like plaques. (S. Scherer, unpublished)	“Neuological deficits were prominent” [206] Epilepsy [152] MRI WMC [156]	[152] originally described in [226]
L90V	Coupling very low, single channel conductance normal. [189] Low junctional conductance and dominant negative effect on endogenous Cx43 mediated NRK coupling. [185]	GJ-like plaques. (reduced nos.) [188, 189]	“Neuro. deficits were prominent” [206]	[152] originally described in [206, 227, 228]
		Disrupted localization (partial apical) in MDCK cells. [186	Epilepsy. [152]
		GJ-like plaques. [185]	Ur. inc. and spastic paraplegia (9/9 patients) [156, 227]
		GJ-like plaques. (S. Scherer, unpublished)
	No dye transfer by scrape load or hemichnnel activity by dye uptake. [188]
H95R			Ur. inc. and spasticity [166] MRI WMC [156]	[166]
V96A			MRI WMC.	[156] originally described in [162]
R101x			Compound hetrozygote G2fs+R101x; See G2fs above.	[173]
K102N		GJ-like plaques. (S. Scherer, unpublished)	Neurologic symptoms. [152] ur. and bowel inc. [156]	[152]
L106P			Spasticity, ur. inc.	[156]
L113P			Spastic paraparesis. [157] UMN, MRI WMC and low signal in grey matter c/w iron deposition.[153]	[157, 212, 229] originally in [153]
			Others note no neurologic findings [229]
I130T	Markedly decreased coupling; single channel size normal. [189, 191]	GJ-like plaques. [191]	Spastic para- or tetraparesis; epilepsy, ur Inc. MRI cerebellum/midbrain atrophy or hypoplasia [167]	[152, 167]
	No dye transfer by scrape load or hemichannel activity by dye uptake. [188]	GJ-like plaques (very reduced). [189]
		GJ-like plaques (slightly reduced). [188]
K134E	Markedly decreased or absent coupling; reduced single channel size (54 pS) [191] Reduced coupling. [189]	GJ-like plaques. [191]	“Neurologic symptoms.” [152] UMN, MRI WMC. [156]	[152]
		GJ-like plaques (very reduced). [189]
K134N	Reduced coupling.[189]	GJ-like plaques (very reduced). [189]	UMN. [156]	[212] probably described previously[230]
G138R	No homotypic,coupling, shifted Gj-Vj relation in hetrotypic with Cx43-EGFP.	GJ-like plaques. [191]	4 generations 1 and 2: no neurologic findings. 3 and 4: spastic bladder paraparesis, square wave jerks and intention tremor presented 2nd to 4th decade. documented WMC on MRI [168] UMN, ur. inc., MRI WMC. [156]	[152] originally described in [168, 206]
	Increased hemichannel activity no neurobiotin transfer[193] [187]	GJ-like plaques and cytopasmic. [187]
	No homotypic coupling. [190, 191] Dominant negative effect on endogenous Cx43 in NRK cells [190] and Hela and N2a cells. [224]
T154A			Mild psychomotor delay and WMC on MRI scan. [231] Gait abnl, UMN, ur. inc., MRI WMC. [156]	[156, 231]
T154N			Spastic paraparesis, inc., tremor. [157]	[157]
V216L	Decreased coupling in patient fibroblasts. [169]	Partial overlap with Golgi marker (but also some WT in Golgi distribution) in patient fibroblasts. [169]	Spasticity, WMC on MRI.[172]	[152, 169] originally described in [172, 206]
	No conductance and dominant negative effect on endogenous Cx43 mediated NRK coupling. [185]	Few GJ-like plaques partial intracellular retention [185]	Gastrointestinal hypomotility, neurogenic bladder, lost ambulation at age 54; hyperreflexia, spasticity. [169]
		GJ-like plaques. (S. Scherer, unpublished)	UMN, MRI WMC ur. and bowel inc. [156]
S220Y			Developmental and language disorder. [157]	[157]
No identified mutation
?			Spasticity.	[158]
?			Severe spasticity.	[159]
?			Spastic tetraparesis.	[160]
?			Spastic paraparesis, nystagmus.	[161]
?			Spastic paraparesis and decreased signal c/w iron deposition in globus pallidus on MRI.	[232]
?			21 YO F spastic paraparesis MRI WMC and low signal in grey matter c/w iron deposition.	[164]
?			MRI diffuse WMC, Abnl low signal in globus pallidus, substantia nigra without calcification on CT c/w iron deposition.	[165]

WMC- white matter changes, typically increase signal on T2 weighted imaging. c/w-consistent with. GJ-gap junction. YO-years old. abnl-abnormal. nl-normal. h/o-history of. G_j-V_j – normalized conductance-voltage relation. UMN-spasticity/hyperreflexia. ur inc-urinary incontinence. neuro-neurological.