Amyotrophic lateral sclerosis/motor neuron disease
Gene: CHMP2BComment on list classification: Kept as red due to expert review. Not present on the NHNN NGS gene panel for ALS, and only found in one source under the ALS phenotype.Created: 15 Jun 2016, 1:44 p.m.
Defects in CHMP2B were originally reported in autosomal dominant FTD. The G>C single nucleotide change in the acceptor splice site of exon 6 of CHMP2B affected mRNA splicing, resulting in two aberrant transcripts: inclusion of the 201-bp intronic sequence between exons 5 and 6, or a short deletion of 10bp from the 5′ end of exon 6. Expression of mutant CHMP2B protein in cells resulted in aberrant structures dispersed throughout the cytosol and the ectopic expression of CHMP2BIntron5 in cortical neurons caused dendritic retraction prior to neurodegeneration.
Sequence analysis of the entire coding region and intron/exon boundaries of CHMP2B from 433 ALS cases identified point mutations in four cases (0.9%)
Miss-sense variants only identified. The phenotype appears to represent a lower motor neuron variant in these cases, however, the present study has not been able to document the segregation of CHMP2B in multiple affected members of specific pedigrees in ALS. CMMP2B may act as a modifier.
Created: 9 Jun 2016, 8:15 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
Publications
Mode of pathogenicity
Other
Promoted to version 1 on 19th December 2016 following external review and internal curation
This gene has been classified as Red List (Low Evidence).
This gene has been classified as Red List (Low Evidence).
Publications for CHMP2B were set to PMID: 20352044 - "We conclude that in a population drawn from North of England pathogenic CHMP2B mutations are found in approximately 1% of cases of ALS and 10% of those with lower motor neuron predominant ALS. We provide a body of evidence indicating the likely pathogenicity of the reported gene alterations. However, absolute confirmation of pathogenicity requires further evidence, including documentation of familial transmission in ALS pedigrees which might be most fruitfully explored in cases with a LMN predominant phenotype."
Publications for CHMP2B were set to 20352044
Mode of pathogenicity for CHMP2B was changed to Other - please provide details in the comments
Mode of inheritance for CHMP2B was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
CHMP2B was added to Amyotrophic lateral sclerosis/motor neuron diseasepanel. Source: Radboud University Medical Center, Nijmegen
CHMP2B was added to Amyotrophic lateral sclerosis/motor neuron diseasepanel. Sources: Radboud University Medical Center, Nijmegen