TABLE 1.

Phenotypic and structural alterations in human and mouse ion channel gene loss-of-function mutations.

Gene name (channel name)	Citations	Observed phenotype in human	Structural changes in humans (on brain imaging unless otherwise specified)	Observed phenotype in mouse	Structural changes in mouse
KCNMA1 (BK, KCa1.1)	Meredith et al., 2004; Sausbier et al., 2004; Liang et al., 2019; Du et al., 2020; Liang et al., 2022	Liang–Wang syndrome: Death in early onset cases due to a multiple visceral malformation syndrome, craniofacial dysmorphism Developmental delay with speech delay, and ataxia in milder cases	Progressive cerebellar atrophy that is variable but sometimes severe Mild cerebral atrophy Thin corpus callosum	Tremor Abnormal gait Decreased time to fall (rotarod) Overactive bladder	None noted in Kcnma1 knockout
KCNN2 (SK, KCa2.2)	Callizot et al., 2001; Shakkottai et al., 2004; Szatanik et al., 2008; Mochel et al., 2020	Developmental delay Early onset cerebellar ataxia Extrapyramidal symptoms	Diffuse periventricular white matter changes Cerebellar atrophy (Mochel personal communication in initially identified case)	Frissonnant: Decreased time to fall (rotarod) Decreased locomotor activity Tremor Kcnn2 knockout: Tremor Kcnn2 dominant-negative suppression: Decreased time to fall (rotarod) Gait ataxia Tremor	None noted in any model
KCNC3 (Kv3.3)	Herman-Bert et al., 2000; Espinosa et al., 2001; Waters et al., 2006; Hurlock et al., 2008	Childhood-onset ataxia or late-onset ataxia Cognitive delay	Global cerebellar volume loss	Decreased time to fall (rotarod) Myoclonus Ethanol hypersensitivity	None noted in Kcnc3 knockout
KCND3 (Kv4.3)	Niwa et al., 2008; Duarri et al., 2012; Lee et al., 2012	Slowly progressive cerebellar ataxia Urinary urgency, incontinence	Mild cerebellar atrophy, Purkinje neuron loss at autopsy (one case)	No neurologic deficits	None noted in Kcnd3 knockout
ITPR1 (IP3 receptor 1)	Matsumoto et al., 1996; Miyoshi et al., 2001; van de Leemput et al., 2007; Iwaki et al., 2008; Sugawara et al., 2013	Cerebellar ataxia Head tremor	Cerebellar atrophy without brainstem involvement	Early death in global knockout with ataxia and seizures Cerebellar ataxia in Purkinje neuron specific knockout	No structural changes noted Increase in dendritic spine density with simplification of dendrites in Purkinje neuron specific deletion
CACNA1G (Cav3.1)	Chemin et al., 2018; Coutelier et al., 2015; Morino et al., 2015; Kimura et al., 2017; Li et al., 2018; Hashiguchi et al., 2019; Barresi et al., 2020	Infantile or childhood-onset cerebellar ataxia, global developmental delay in gain-of-function mutations Late onset ataxia with loss-of-function mutations	Childhood-onset cerebellar atrophy Cerebellar atrophy with Purkinje neuron loss at autopsy	Decreased time to fall (rotarod) Increased gait width	Late Purkinje cell loss in loss-of-function mutation
CACNA (Cav2.1)	Ophoff et al., 1996; Zhuchenko et al., 1997; Jun et al., 1999; Fletcher et al., 2001; Pietrobon, 2002; Du et al., 2013; Reinson et al., 2016; Jen and Wan, 2018	Episodic ataxia type 2: episodes that respond to acetazolamide and spontaneously remit in later life Allelic with Familial hemiplegic and Spinocerebellar ataxia type 6	Variable and selective atrophy of the cerebellar vermis in some cases late in life	Low body weight Decreased lifespan Decreased time to fall (rotarod) Ataxia Seizure	Early Purkinje, granule and Golgi cell loss