Association of A Novel Splice Site Mutation in P/Q-Type Calcium Channels with Childhood Epilepsy and Late-Onset Slowly Progressive Non-Episodic Cerebellar Ataxia

被引:16
作者
Stendel, Claudia [1 ,2 ]
D'Adamo, Maria Cristina [3 ]
Wiessner, Manuela [1 ]
Dusl, Marina [1 ]
Cenciarini, Marta [4 ]
Belia, Silvia [5 ]
Nematian-Ardestani, Ehsan [3 ]
Bauer, Peter [6 ]
Senderek, Jan [1 ]
Klopstock, Thomas [1 ,2 ,7 ]
Pessia, Mauro [3 ,8 ]
机构
[1] Ludwig Maximilians Univ Munchen, Univ Hosp, Friedrich Baur Inst, Dept Neurol, D-80336 Munich, Germany
[2] German Ctr Neurodegenerat Dis DZNE, D-81377 Munich, Germany
[3] Univ Malta, Fac Med, Dept Physiol & Biochem, MSD-2080 Msida, Malta
[4] Univ Perugia, Dept Expt Med, Sect Physiol & Biochem, Sch Med, I-06132 Perugia, Italy
[5] Univ Perugia, Dept Chem Biol & Biotechnol, I-06132 Perugia, Italy
[6] Univ Tubingen, Inst Med Genet & Appl Genom, D-72076 Tubingen, Germany
[7] Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany
[8] United Arab Emirates Univ, Dept Physiol, POB 17666, Al Ain, U Arab Emirates
关键词
absence epilepsy; cerebellar ataxia; CACNA1A mutation; next-generation sequencing; P/Q-type calcium channel; SPINOCEREBELLAR ATAXIA; MISSENSE MUTATION; CACNA1A GENE; PHENOTYPE; MIGRAINE; CA(V)2.1; FAMILY; SCA6; CA2+;
D O I
10.3390/ijms21113810
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Episodic ataxia type 2 (EA2) is characterized by paroxysmal attacks of ataxia with typical onset in childhood or early adolescence. The disease is associated with mutations in the voltage-gated calcium channel alpha 1A subunit (Cav2.1) that is encoded by the CACNA1A gene. However, previously unrecognized atypical symptoms and the genetic overlap existing between EA2, spinocerebellar ataxia type 6, familial hemiplegic migraine type 1, and other neurological diseases blur the genotype/phenotype correlations, making a differential diagnosis difficult to formulate correctly and delaying early therapeutic intervention. Here we report a new clinical phenotype of a CACNA1A-associated disease characterized by absence epilepsy occurring during childhood. However, much later in life the patient displayed non-episodic, slowly progressive gait ataxia. Gene panel sequencing for hereditary ataxias led to the identification of a novel heterozygous CACNA1A mutation (c.1913 + 2T > G), altering the donor splice site of intron 14. This genetic defect was predicted to result in an in-frame deletion removing 44 amino acids from the voltage-gated calcium channel Cav2.1. An RT-PCR analysis of cDNA derived from patient skin fibroblasts confirmed the skipping of the entire exon 14. Furthermore, two-electrode voltage-clamp recordings performed from Xenopus laevis oocytes expressing a wild-type versus mutant channel showed that the genetic defect caused a complete loss of channel function. This represents the first description of distinct clinical manifestations that remarkably expand the genetic and phenotypic spectrum of CACNA1A-related diseases and should be considered for an early diagnosis and effective therapeutic intervention.
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页数:13
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