CACNA1H Mutations in Autism Spectrum Disorders

Abstract

Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by impaired social interaction, communication skills, and restricted and repetitive behavior. The genetic causes for autism are largely unknown. Previous studies implicate CACNA1C (L-type Ca V 1.2) calcium channel mutations in a disorder associated with autism (Timothy syndrome). Here, we identify missense mutations in the calcium channel gene CACNA1H (T-type Ca V 3.2) in 6 of 461 individuals with ASD. These mutations are located in conserved and functionally relevant domains and are absent in 480 ethnically matched controls (p ‫؍‬ 0.014, Fisher's exact test). Non-segregation within the pedigrees between the mutations and the ASD phenotype clearly suggest that the mutations alone are not responsible for the condition. However, functional analysis shows that all these mutations significantly reduce Ca V 3.2 channel activity and thus could affect neuronal function and potentially brain development. We conclude that the identified mutations could contribute to the development of the ASD phenotype.Autism spectrum disorders affect ϳ0.5% of children in the general population and cause great morbidity (1, 2). Epidemiologic studies estimate that up to 400,000 children are affected in the United States alone (3). The primary features of ASD are severe difficulties in social interaction, communication deficits, and unusual behaviors, including repetitive and/or ritualistic actions. There is considerable variation in the severity of phenotypes in autism spectrum disorders, which include autism, Asperger syndrome, childhood disintegrative disorder, Rett syndrome, and pervasive developmental disorder not otherwise specified. Despite the high prevalence and importance of autism spectrum disorders, very little is known about underlying molecular and cellular mechanisms (4).Timothy syndrome (TS) 3 is a complex physiological and developmental disorder, which includes autism spectrum disorders. We discovered that TS resulted from a recurrent, de novo CACNA1C calcium (Ca 2ϩ ) channel mutation, G406R. Our findings that individuals with TS met the criteria for autism, or had severe deficits of language and social development, suggest that abnormal Ca 2ϩ signaling may cause these disorders (5). Based on these results we hypothesized that mutations in other Ca 2ϩ channel genes might be responsible for non-syndromic forms of ASD.Neuroanatomical studies of autistic patients have found histological abnormalities in the major regions of the limbic system including the hippocampus and amygdala and in the cerebellum and cerebral cortex (6). Ca V 3.2, a T-type calcium channel encoded by the CACNA1H gene, is abundantly expressed in these and other regions. T-type Ca 2ϩ channels activate with relatively small depolarization of the neuron membrane triggering low threshold spikes that contribute to rebound burst firing and oscillatory behavior in central neurons (7). In the thalamus, this behavior maintains normal transitions in sensory gating, sleep, and arousal (8,...

The I–II Loop Controls Plasma Membrane Expression and Gating of Cav3.2 T-Type Ca2+Channels: A Paradigm for Childhood Absence Epilepsy Mutations

“…Therefore, the present results provide a unifying mechanism by which polymorphisms cause a gain in T-channel function that would contribute to seizure susceptibility. The corollary may also be important: polymorphisms in CACNA1H that decrease channel activity were found in patients with autism spectrum disorders (ASD) (Splawski et al, 2006). As observed in CAE patients, some SNPs found only in affected patients were always found in conjunction with neighboring SNPs found in control patients (in CAE, G773D with R778C; in ASD, A1874V with R1871Q).…”

Autism throughout genetics: Perusal of the implication of ion channels

“…Four heterozygous missense variations in CACNA1H gene, encoding the Ca v 3.2 subunit of T‐type channels, were found associated with decreased channel activity in six of 461 autistic patients. This decrease could be a result of abnormal trafficking of the channel (Splawski et al., 2006; Table 2). Variations in the CACNA1H gene have also been associated with childhood absence epilepsy (Splawski et al., 2006).…”

“…This decrease could be a result of abnormal trafficking of the channel (Splawski et al., 2006; Table 2). Variations in the CACNA1H gene have also been associated with childhood absence epilepsy (Splawski et al., 2006). Another α 1 subunit of the T‐type calcium channel‐encoding gene ( CACNA1G ) mapped at 17q11–q21 region was found to contain SNPs (rs12603122, rs757415, rs12603112, and rs198547) in patients with ASD (Lu, Dai, Martinez‐Agosto, & Cantor, 2012).…”

Autism genetics: searching for specificity and convergence

“…NMDA receptors are ionotropic ion channels that are critical regulators of activity-dependent synaptic plasticity. Other notable ASD candidate genes that code for ion channels are the ionotropic glutamate receptors GRIK2 [106] and GRIA3 [107] and the voltage-dependent calcium channel subunits CACNA1C [70] and CACNA1H [108]. …”