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Published on: October 10, 2017
Copy number variations involving the microtubule-associated protein tau in human diseases
Anne Rovelet-Lecrux1, Dominique Campion
1Inserm, U1079, Rouen, France. anne.roveletlecrux@univrouen.fr
Abstract:
Mutations of the MAPT (microtubule-associated protein tau) gene are associated with FTLD (frontotemporal lobar degeneration) with tau pathology. These mutations result in a decreased ability of tau to bind MTs (microtubules), an increased production of tau with four MT-binding repeats or enhanced tau aggregation. In two FTLD patients, we recently described CNVs (copy number variations) affecting the MAPT gene, consisting of a partial deletion and a complete duplication of the gene. The partial deletion resulted in a truncated protein lacking the first MT-binding domain, which had a dramatic decrease in the binding to MTs but acquired the ability to bind MAP (microtubule-associated protein) 1-B. In this case, tauopathy probably resulted from both a loss of normal function and a gain of function by which truncated tau would sequester another MAP. In the other FTLD patient, the complete duplication might result in the overexpression of tau, which in the mouse model induces axonopathy and tau aggregates reminiscent of FTLD-tau pathology. Interestingly, the same rearrangement was also described in several children with mental retardation, autism spectrum disorders and dysmorphic features, as well as in a schizophrenic patient. Finally, complete deletions of the MAPT gene have been associated with mental retardation, hypotonia and facial dysmorphism.
Insights
Copy number variations in the MAPT gene are linked to frontotemporal lobar degeneration (FTLD). These genetic changes, including deletions and duplications, impact tau protein function and aggregation, contributing to neurodegenerative diseases.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Mutations in the MAPT gene are implicated in frontotemporal lobar degeneration (FTLD) with tau pathology.
- MAPT gene mutations can alter tau's microtubule-binding ability, increase four-repeat tau production, or enhance tau aggregation.
Purpose of the Study:
- To investigate the impact of copy number variations (CNVs) affecting the MAPT gene in FTLD patients.
- To understand the functional consequences of MAPT gene partial deletion and complete duplication.
Main Methods:
- Description of CNVs (partial deletion, complete duplication) in the MAPT gene in two FTLD patients.
- Analysis of the functional impact of the resulting truncated tau protein on microtubule binding.
- Examination of tau overexpression effects in a mouse model.
Main Results:
- A MAPT partial deletion led to a truncated tau protein with reduced microtubule binding but gained binding to MAP 1-B, suggesting loss and gain of function.
- A MAPT complete duplication in another FTLD patient may cause tau overexpression, leading to axonopathy and tau aggregates in a mouse model.
- Similar MAPT duplications were observed in individuals with developmental disorders and schizophrenia.
Conclusions:
- CNVs affecting the MAPT gene can cause FTLD through altered tau function and aggregation.
- MAPT gene rearrangements are associated with a spectrum of neurological and psychiatric conditions beyond FTLD.
- Understanding these genetic variations is crucial for diagnosing and potentially treating tauopathies.
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01:31Translation
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Translation Produces the Building Blocks of Life
01:31Translation
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
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