Novel mutation in optineurin causing aggressive ALS+/−frontotemporal dementia

Abstract

ObjectiveMutations in optineurin (OPTN) have been identified in familial and sporadic amyotrophic lateral sclerosis (ALS). We screened a cohort of Chinese patients for mutations in optineurin. We also performed an extensive literatures review of all mutations in optineurin identified previously to detect genotype–phenotype associations.MethodsAll 16 exons of the OPTN gene in a cohort of 15 familial ALS indexes and 275 sporadic ALS patients of Chinese origin were sequenced by targeted next generation sequencing.ResultsTwo known heterozygous missense mutations in the OPTN, c.1481T> G (p.L494W), and c.1546G> C (p.E516Q), as well as one novel heterozygous missense mutation c.1690G> C (p.D564H) were each detected in one sporadic ALS patient. The patient carrying the p.E516Q mutation developed clinical features of ALS‐frontotemporal dementia (FTD) and the patient carrying the p.D564H mutation showed a phenotype of ALS. They both had an aggressive course, with a survival of 18 and 14 months respectively. Literature review showed that the clinical phenotypes in OPTN mutated ALS were not homogeneous, although some individuals showed a relatively slow progression and a long duration, some mutations carriers developed an aggressive progression and a short survival.Interpretation OPTN mutations contribute to ALS in Chinese population and account for 0.8% of sporadic ALS patients and 1.5% of familial ALS in the pooled Chinese ALS cohorts. Mutations in optineurin can cause aggressive ALS+/−FTD.

A Systematic Review of Genotype–Phenotype Correlation across Cohorts Having Causal Mutations of Different Genes in ALS

“…For age of onset, motor neuron impairments, disease duration, and FTD, the weighted mean ± SD, and weighted percentages are given, taking into account the numbers of patients studied. Data for each gene were collected from the following reference studies, then summarized: hnRNPA1: [ 168 ]; SETX: [ 169 , 170 , 171 , 172 , 173 ]; SOD1: [ 24 , 92 , 160 , 161 , 171 , 172 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 ]; TBK1: [ 189 , 190 , 191 , 192 ]; FUS: [ 24 , 92 , 145 , 146 , 148 , 170 , 171 , 172 , 179 , 180 , 187 , 188 , 193 , 194 , 195 , 196 ]; OPTN: [ 171 , 180 , 187 , 197 , 198 , 199 ,…”

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

“…Optineurin and p62 are functionally related to TBK1 and are coded by the OPTN and SQSTM1 genes. Variants in OPTN have been found in 0.5% of FALS and 0.4% of SALS patients of European origin, as well as 2.5% of FALS and 0.7% of SALS patients of Asian origin [ 91 ]. More than 60 ALS-associated variants in OPTN have been reported to date, with around two-fifths belonging to the protein-truncating variant (PTV) category.…”

“…More than 60 ALS-associated variants in OPTN have been reported to date, with around two-fifths belonging to the protein-truncating variant (PTV) category. Furthermore, homozygous or compound heterozygous OPTN variants responsible for ALS were consistently truncating [ 91 ].…”

Multisystem proteinopathy: Where myopathy and motor neuron disease converge

“…Mutations in OPTN , primarily through loss of function, are responsible for over 1% of familial ALS cases, although they were originally associated with autosomal dominant primary open angle glaucoma 96,98,99 . Mutant OPTN associated with ubiquinated inclusions is found in familial ALS attributed to OPTN mutation, while wild type misfolded OPTN is seen in sporadic ALS 100 .…”