DYNC1H1 and Associated Diseases
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Backgrounds of DYNC1H1 Gene
DYNC1H1 is located on chromosome 14q32.31 and the protein encoded by DYNC1H1 belongs to the cytoplasmic dynein heavy chain family. Dyneins are a group of ATPases that activate microtubules and perform biological functions as molecular motors. DYNC1H1 comprises four major protein regions, i.e., tail domains, linker domain, motor domains with AAA domains (ATPases associated with a variety of cellular activities), and the stalk or microtubule-binding domain (MTBD). The dimer formed by DYNC1H1 is the core of the dynein motor complex, which transports cargo along microtubules in a retrograde fashion. DYNC1H1 is highly conserved and is an essential protein in higher eukaryotes because dynein complexes perform housekeeping functions in all cells, including mitotic spindle positioning, nuclear localization, Golgi maintenance, and endosomal dynamics.
Fig.1 Architecture of the dynein complex. (Hoang, 2017)
Functions of DYNC1H1
DYNC1H1 was associated with spinal muscular atrophy, disease mutation, intellectual disability, neurodegeneration, and neuropathy. In neurons, DYNC1H1 is essential for retrograde cargo transport in axons and dendrites as part of the cytoplasmic dynein complex and is therefore involved in neuronal development, morphology, and survival. In mammals, new insights into DYNC1H1 function have come from the description of a set of dynamin heavy chain mouse mutations. Mutations have now been found in humans as well. Both mouse and human data suggest that dynein-heavy chains are essential for the proper functioning of the nervous system, even this one. A single conserved amino acid substitution in the 500-kDa protein also causes neurological abnormalities. Thus, DNYC1H1 may have a broad biological role in the development and maintenance of the nervous system.
Diseases With DYNC1H1 Mutations
DYNC1H1-related disorders are heterogeneous, affecting the development and function of either the central or peripheral nervous system, or both. DYNC1H1 variants have been associated with several neurological and motor neuron pathologies of varying severity; for example, they have recently been associated with upper and lower motor neuron abnormalities, overlapping neurodevelopmental and neuromuscular phenotypes, and other mixed phenotypes. Mutations in the DYNC1H1 have been identified in rare neuromuscular (NMD) and neurodevelopmental (NDD) disorders, such as lower extremity dominant spinal muscular atrophy (SMALED) and autosomal dominant mental retardation syndrome 13 (MRD13).
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Reference
- Hoang, H.T.; et al. DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein-dynactin-cargo adaptor complexes. Proceedings of the National Academy of Sciences. 2017, 114(9): E1597-E1606.
