Intronic pentanucleotide TTTCA repeat insertion in the SAMD12 gene causes familial cortical myoclonic tremor with epilepsy type 1

Zhidong Cen, Zhengwen Jiang, You Chen, Xiaosheng Zheng, Fei Xie, Xiaodong Yang, Xingjiao Lu, Zhiyuan Ouyang, Hongwei Wu, Si Chen, Houmin Yin, Xia Qiu, Shuang Wang, Meiping Ding, Yelei Tang, Feng Yu, Caihua Li, Tao Wang, Hiroyuki Ishiura, Shoji Tsuji & 4 others Chuan Jiao, Chunyu Liu, Jianfeng Xiao, Wei Luo

Research output: Contribution to journalArticle

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Abstract

Familial cortical myoclonic tremor with epilepsy is an autosomal dominant neurodegenerative disease, characterized by cortical tremor and epileptic seizures. Although four subtypes (types 1–4) mapped on different chromosomes (8q24, 2p11.1-q12.2, 5p15.31-p15.1 and 3q26.32-3q28) have been reported, the causative gene has not yet been identified. Here, we report the genetic study in a cohort of 20 Chinese pedigrees with familial cortical myoclonic tremor with epilepsy. Linkage and haplotype analysis in 11 pedigrees revealed maximum two-point logarithm of the odds (LOD) scores from 1.64 to 3.77 (LOD scores in five pedigrees were 43.0) in chromosomal region 8q24 and narrowed the candidate region to an interval of 4.9 Mb. Using whole-genome sequencing, long-range polymerase chain reaction and repeat-primed polymerase chain reaction, we identified an intronic pentanucleotide (TTTCA)n insertion in the SAMD12 gene as the cause, which co-segregated with the disease among the 11 pedigrees mapped on 8q24 and additional seven unmapped pedigrees. Only two pedigrees did not contain the (TTTCA)n insertion. Repeat-primed polymerase chain reaction revealed that the sizes of (TTTCA)n insertion in all affected members were larger than 105 repeats. The same pentanucleotide insertion (ATTTCATTTC)58 has been reported to form RNA foci resulting in neurotoxicity in spinocerebellar ataxia type 37, which suggests the similar pathogenic process in familial cortical myoclonic tremor with epilepsy type 1.

Original languageEnglish (US)
Pages (from-to)2280-2288
Number of pages9
JournalBrain
Volume141
Issue number8
DOIs
StatePublished - Jan 1 2018

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Pedigree
Microsatellite Repeats
Genes
Polymerase Chain Reaction
Spinocerebellar Ataxias
Tremor
Neurodegenerative Diseases
Haplotypes
Epilepsy, Myoclonic, Benign Adult Familial, Type 1
Epilepsy
Chromosomes
Genome
RNA

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Intronic pentanucleotide TTTCA repeat insertion in the SAMD12 gene causes familial cortical myoclonic tremor with epilepsy type 1. / Cen, Zhidong; Jiang, Zhengwen; Chen, You; Zheng, Xiaosheng; Xie, Fei; Yang, Xiaodong; Lu, Xingjiao; Ouyang, Zhiyuan; Wu, Hongwei; Chen, Si; Yin, Houmin; Qiu, Xia; Wang, Shuang; Ding, Meiping; Tang, Yelei; Yu, Feng; Li, Caihua; Wang, Tao; Ishiura, Hiroyuki; Tsuji, Shoji; Jiao, Chuan; Liu, Chunyu; Xiao, Jianfeng; Luo, Wei.

In: Brain, Vol. 141, No. 8, 01.01.2018, p. 2280-2288.

Research output: Contribution to journalArticle

Cen, Z, Jiang, Z, Chen, Y, Zheng, X, Xie, F, Yang, X, Lu, X, Ouyang, Z, Wu, H, Chen, S, Yin, H, Qiu, X, Wang, S, Ding, M, Tang, Y, Yu, F, Li, C, Wang, T, Ishiura, H, Tsuji, S, Jiao, C, Liu, C, Xiao, J & Luo, W 2018, 'Intronic pentanucleotide TTTCA repeat insertion in the SAMD12 gene causes familial cortical myoclonic tremor with epilepsy type 1', Brain, vol. 141, no. 8, pp. 2280-2288. https://doi.org/10.5582/bst.2016.01140
Cen, Zhidong ; Jiang, Zhengwen ; Chen, You ; Zheng, Xiaosheng ; Xie, Fei ; Yang, Xiaodong ; Lu, Xingjiao ; Ouyang, Zhiyuan ; Wu, Hongwei ; Chen, Si ; Yin, Houmin ; Qiu, Xia ; Wang, Shuang ; Ding, Meiping ; Tang, Yelei ; Yu, Feng ; Li, Caihua ; Wang, Tao ; Ishiura, Hiroyuki ; Tsuji, Shoji ; Jiao, Chuan ; Liu, Chunyu ; Xiao, Jianfeng ; Luo, Wei. / Intronic pentanucleotide TTTCA repeat insertion in the SAMD12 gene causes familial cortical myoclonic tremor with epilepsy type 1. In: Brain. 2018 ; Vol. 141, No. 8. pp. 2280-2288.
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abstract = "Familial cortical myoclonic tremor with epilepsy is an autosomal dominant neurodegenerative disease, characterized by cortical tremor and epileptic seizures. Although four subtypes (types 1–4) mapped on different chromosomes (8q24, 2p11.1-q12.2, 5p15.31-p15.1 and 3q26.32-3q28) have been reported, the causative gene has not yet been identified. Here, we report the genetic study in a cohort of 20 Chinese pedigrees with familial cortical myoclonic tremor with epilepsy. Linkage and haplotype analysis in 11 pedigrees revealed maximum two-point logarithm of the odds (LOD) scores from 1.64 to 3.77 (LOD scores in five pedigrees were 43.0) in chromosomal region 8q24 and narrowed the candidate region to an interval of 4.9 Mb. Using whole-genome sequencing, long-range polymerase chain reaction and repeat-primed polymerase chain reaction, we identified an intronic pentanucleotide (TTTCA)n insertion in the SAMD12 gene as the cause, which co-segregated with the disease among the 11 pedigrees mapped on 8q24 and additional seven unmapped pedigrees. Only two pedigrees did not contain the (TTTCA)n insertion. Repeat-primed polymerase chain reaction revealed that the sizes of (TTTCA)n insertion in all affected members were larger than 105 repeats. The same pentanucleotide insertion (ATTTCATTTC)58 has been reported to form RNA foci resulting in neurotoxicity in spinocerebellar ataxia type 37, which suggests the similar pathogenic process in familial cortical myoclonic tremor with epilepsy type 1.",
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T1 - Intronic pentanucleotide TTTCA repeat insertion in the SAMD12 gene causes familial cortical myoclonic tremor with epilepsy type 1

AU - Cen, Zhidong

AU - Jiang, Zhengwen

AU - Chen, You

AU - Zheng, Xiaosheng

AU - Xie, Fei

AU - Yang, Xiaodong

AU - Lu, Xingjiao

AU - Ouyang, Zhiyuan

AU - Wu, Hongwei

AU - Chen, Si

AU - Yin, Houmin

AU - Qiu, Xia

AU - Wang, Shuang

AU - Ding, Meiping

AU - Tang, Yelei

AU - Yu, Feng

AU - Li, Caihua

AU - Wang, Tao

AU - Ishiura, Hiroyuki

AU - Tsuji, Shoji

AU - Jiao, Chuan

AU - Liu, Chunyu

AU - Xiao, Jianfeng

AU - Luo, Wei

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Familial cortical myoclonic tremor with epilepsy is an autosomal dominant neurodegenerative disease, characterized by cortical tremor and epileptic seizures. Although four subtypes (types 1–4) mapped on different chromosomes (8q24, 2p11.1-q12.2, 5p15.31-p15.1 and 3q26.32-3q28) have been reported, the causative gene has not yet been identified. Here, we report the genetic study in a cohort of 20 Chinese pedigrees with familial cortical myoclonic tremor with epilepsy. Linkage and haplotype analysis in 11 pedigrees revealed maximum two-point logarithm of the odds (LOD) scores from 1.64 to 3.77 (LOD scores in five pedigrees were 43.0) in chromosomal region 8q24 and narrowed the candidate region to an interval of 4.9 Mb. Using whole-genome sequencing, long-range polymerase chain reaction and repeat-primed polymerase chain reaction, we identified an intronic pentanucleotide (TTTCA)n insertion in the SAMD12 gene as the cause, which co-segregated with the disease among the 11 pedigrees mapped on 8q24 and additional seven unmapped pedigrees. Only two pedigrees did not contain the (TTTCA)n insertion. Repeat-primed polymerase chain reaction revealed that the sizes of (TTTCA)n insertion in all affected members were larger than 105 repeats. The same pentanucleotide insertion (ATTTCATTTC)58 has been reported to form RNA foci resulting in neurotoxicity in spinocerebellar ataxia type 37, which suggests the similar pathogenic process in familial cortical myoclonic tremor with epilepsy type 1.

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