Motor Neurone Disease
Gene: TUBA4A
Multiple individuals reported. However, some are identified as part of cohorts and no segregation data is available (PMID 25374358). Two families reported in PMID 28069311, however one of the individuals had an alternative diagnosis. No variants in this gene identified in a cohort of 814 FTD patients from Spain.Created: 25 Sep 2020, 4:26 a.m. | Last Modified: 25 Sep 2020, 4:26 a.m.
Panel Version: 0.54
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Amyotrophic lateral sclerosis 22 with or without frontotemporal dementia, MIM# 616208
Publications
At least 13 probands reported with ALS or phenotype including motor neurone involvement. Limited segregation evidence and mechanism of disease not established - toxic gain of function, dominant negative, or loss of function suggested
PMID: 25374358 - 7 rare TUBA4A variants OR = 36 [95% CI: 10–210], p = 4.3 × 10−7, Pcorrected = 4.2 × 10−3 in an FALS cohort. Included 1 nonsense (W407X in last exon) and 6 missense variants. FALS cases n=635, controls n=5,510. T145P variant segregated with disease within the family, while K430N was not detected in an affected first cousin of the sequenced proband (?phenocopy). Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability - suggesting a dominant negative mechanism of disease.
PMID: 25893256 - 4 Italian sporadic ALS cases with rare TUBA4A variants (3 missense & 1 splice variant). Minigene assay demonstrates c.226+4A>G causes exon 2 skipping which is expected to a frameshift and NMD. Loss of function is not an established mechanism of ALS in relation to TUBA4A.
PMID: 28069311 - rare missense (Thr381Met) detected in 2 siblings with ALS, but both had the C9orf72 expansion
PMID: 38463699 - reduced TUBA4A protein expression in familial and sporadic ALS brain tissue. Knockout zebrafish has a motor axonopathy and motor behavior defects reflecting a motor neuron disease phenotype
PMID: 38884572 - Multicentre cohort of 12 patients from 11 unrelated families presenting with ataxia age of onset 2-60 yrs (9 different missense variants). Amyotrophy or upper limb muscular weakness in 2/12, 16.6%.Created: 3 Jul 2024, 8:15 a.m. | Last Modified: 3 Jul 2024, 8:15 a.m.
Panel Version: 1.21
Comment on list classification: >3 independent ALS cases reportedCreated: 18 Dec 2019, 7:27 a.m. | Last Modified: 18 Dec 2019, 7:27 a.m.
Panel Version: 0.28
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
amyotrophic lateral sclerosis type 22 MONDO:0014531
Publications
Publications for gene: TUBA4A were set to 25374358; 25893256; 28069311; 38463699; 38884572; 26675813
Publications for gene: TUBA4A were set to 28069311; 25374358; 26675813
Gene: tuba4a has been classified as Green List (High Evidence).
Gene: tuba4a has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: TUBA4A were changed from to Amyotrophic lateral sclerosis 22 with or without frontotemporal dementia, MIM# 616208
Publications for gene: TUBA4A were set to
Mode of inheritance for gene: TUBA4A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Gene: tuba4a has been classified as Amber List (Moderate Evidence).
gene: TUBA4A was added gene: TUBA4A was added to Motor neuron disease MND_MelbourneGenomics_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services,Melbourne Genomics Health Alliance Complex Neurology Flagship Mode of inheritance for gene: TUBA4A was set to Unknown