A recessive S174X mutation in Optineurin causes amyotrophic lateral sclerosis through a loss of function via allele-specific nonsense-mediated decay.

Loss of function (LoF) mutations in Optineurin can cause recessive amyotrophic lateral sclerosis (ALS) with some heterozygous LoF mutations associated with dominant ALS. The molecular mechanisms underlying the variable inheritance pattern associated with OPTN mutations have remained elusive. We identified that affected members of a consanguineous Middle Eastern ALS kindred possessed a novel homozygous p.

ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function.

Mutations in TANK binding kinase 1 (TBK1) have been linked to amyotrophic lateral sclerosis. Some TBK1 variants are nonsense and are predicted to cause disease through haploinsufficiency; however, many other mutations are missense with unknown functional effects. We exome sequenced 699 familial amyotrophic lateral sclerosis patients and identified 16 TBK1 novel or extremely rare protein-changing variants.

Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the gene in 13 individuals.

Non-nuclear Pool of Splicing Factor SFPQ Regulates Axonal Transcripts Required for Normal Motor Development.

Recent progress revealed the complexity of RNA processing and its association to human disorders. Here, we unveil a new facet of this complexity. Complete loss of function of the ubiquitous splicing factor SFPQ affects zebrafish motoneuron differentiation cell autonomously.

C9ORF72 and UBQLN2 mutations are causes of amyotrophic lateral sclerosis in New Zealand: a genetic and pathologic study using banked human brain tissue.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, which causes progressive and eventually fatal loss of motor function. Here, we describe genetic and pathologic characterization of brain tissue banked from 19 ALS patients over nearly 20 years at the Department of Anatomy and the Centre for Brain Research, University of Auckland, New Zealand. We screened for mutations in SOD1, TARDBP, FUS, and C9ORF72 genes and for neuropathology caused by phosphorylated TDP-43, dipeptide repeats (DPRs), and ubiquilin.

The CHCHD10 P34S variant is not associated with ALS in a UK cohort of familial and sporadic patients.

Mutations in CHCHD10 have recently been reported as a cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. To address the genetic contribution of CHCHD10 to ALS, we have screened a cohort of 425 UK ALS ± frontotemporal dementia patients and 576 local controls in all coding exons of CHCHD10 by Sanger sequencing. We identified a previously reported p.

Novel mutations support a role for Profilin 1 in the pathogenesis of ALS.

Mutations in the gene encoding profilin 1 (PFN1) have recently been shown to cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. We sequenced the PFN1 gene in a cohort of ALS patients (n = 485) and detected 2 novel variants (A20T and Q139L), as well as 4 cases with the previously identified E117G rare variant (∼ 1.2%).