ANXA11 mutations prevail in Chinese ALS patients with and without cognitive dementia.

Abstract

OBJECTIVE:

To investigate the genetic contribution of ANXA11, a gene associated with amyotrophic lateral sclerosis (ALS), in Chinese ALS patients with and without cognitive dementia.

METHODS:

Sequencing all the coding exons of ANXA11 and intron-exon boundaries in 18 familial amyotrophic lateral sclerosis (FALS), 353 unrelated sporadic amyotrophic lateral sclerosis (SALS), and 12 Chinese patients with ALS-frontotemporal lobar dementia (ALS-FTD). The transcripts in peripheral blood generated from a splicing mutation were examined by reverse transcriptase PCR.

RESULTS:

We identified 6 nonsynonymous heterozygous mutations (5 novel and 1 recurrent), 1 splice site mutation, and 1 deletion of 10 amino acids (not accounted in the mutant frequency) in 11 unrelated patients, accounting for a mutant frequency of 5.6% (1/18) in FALS, 2.3% (8/353) in SALS, and 8.3% (1/12) in ALS-FTD. The deletion of 10 amino acids was detected in 1 clinically undetermined male with an ALS family history who had atrophy in hand muscles and myotonic discharges revealed by EMG. The novel p. P36R mutation was identified in 1 FALS index, 1 patient with SALS, and 1 ALS-FTD. The splicing mutation (c.174-2A>G) caused in-frame skipping of the entire exon 6. The rest missense mutations including p.D40G, p.V128M, p.S229R, p.R302C and p.G491R were found in 6 unrelated patients with SALS.

CONCLUSIONS:

The ANXA11 gene is one of the most frequently mutated genes in Chinese patients with SALS. A canonical splice site mutation leading to skipping of the entire exon 6 further supports the loss-of-function mechanism. In addition, the study findings further expand the ANXA11 phenotype, first highlighting its pathogenic role in ALS-FTD.

• Authors: Kang Zhang, Qing Liu, Keqiang Liu, Dongchao Shen, Hongfei Tai, Shi Shu, Qingyun Ding, Hanhui Fu, Shuangwu Liu, Zhili Wang, Xiaoguang Li, Mingsheng Liu, Xue Zhang, Liying Cui
• Journal: Neurology. Genetics (Neurol Genet) Vol. 4 Issue 3 Pg. e237 (Jun 2018) ISSN: 2376-7839 [Print] United States
• PMID: 29845112 (Publication Type: Journal Article)