Early-onset Dementia

Gene: TUBA4A

Green List (high evidence)

At least 8 cases reported with dementia or cognitive decline, segregation evidence in a large family. The mechanism of disease is unclear - possibly loss of function or dominant negative.
PMID: 25374358 - 2/7 cases with FTD & ALS & 1 ALS case with a family history of FTD with rare TUBA4A variants
PMID: 28069311, 35327632 - c.187del (p.Arg64Glyfs*90) identified in an FTD case. PTC created in final exon, not expected to undergo NMD. Loss of mRNA expression and reduced protein expression in patient brain samples, suggestive of haploinsufficiency as the mechanism of disease.
PMID: 34169147 - R105C segregates with bvFTD/unspecified dementia in 6 individuals. Immunoblotting of temporal cortex tissue of 2 cases in the family showed reduced TUBA4A protein expression. In functional studies the R105C variant at least partially disrupts tubulin function, preventing the incorporation of the mutant protein into microtubules
PMID: 38884572 - Multicentre cohort of 12 patients from 11 unrelated families presenting with ataxia age of onset 2-60 yrs (9 different missense variants). Cognitive decline in 4/12, 33,3%.
PMID: 33760283 - Parkinson’s disease case (Dx 47 yrs) with a nonsense variant (R79X) which demonstrated loss of expression.

Created: 3 Jul 2024, 8:04 a.m. | Last Modified: 3 Jul 2024, 8:04 a.m.

Panel Version: 1.22

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Inherited neurodegenerative disorder MONDO:0024237, TUBA4A-related

Publications

• 25374358
• 28069311
• 35327632
• 34169147
• 38884572
• 33760283

I don't know

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, 4:24 a.m. | Last Modified: 25 Sep 2020, 4:24 a.m.

Panel Version: 0.117

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Amyotrophic lateral sclerosis 22 with or without frontotemporal dementia, MIM# 616208

Publications

• 28069311
• 25374358
• 26675813