HCFC1 and Associated Diseases
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Backgrounds of HCFC1
HCFC1 is a transcriptional coregulator that interacts with a variety of proteins, including transcription factors, to regulate different biological processes such as cell proliferation, migration, and cell death. It was originally discovered as a host transcription factor during the latent reactivation of Herpes Simplex Virus (HSV) infection. However, HCFC1 is not a traditional transcription factor because it lacks a DNA binding domain and requires interaction with other proteins to regulate the expression of downstream effectors. The HCFC1 protein has several conserved protein domains, including a kelch protein interaction domain, a fibronectin domain, and an HCF domain that contains cleavage sites that facilitate protein processing and function. This protein is essential for cell viability and exhibits similar activity in many species.
Fig.1 Schematic representation of an HCFC1-containing transcription initiation complex. (Michaud, 2013)
Functions of HCFC1
HCFC1 is known to interact with diverse proteins to regulate a variety of processes, including the cell cycle, proliferation, and transcription, and exerts control on targets through THAPs, specifically THAP11. Thus, mutations that interfere with the interaction between HCFC1 and its transcriptional regulatory partners may affect the expression of a large number of downstream effectors. The discovery of variants in the regulatory regions of HCFC1 as a possible cause of nonsyndromic intellectual disability has implicated HCFC1 in brain development and function. HCFC1 is also a key transcriptional coactivator of the retinoblastoma protein, a potent inhibitor of S-phase genes. The location of HCFC1 on human chromosome X, combined with the existence of several males with apparent cblC deficiency and no MMACHC mutations, led us to predict that this disorder might represent an X-linked disorder affecting males.
Mutations in the HCFC1 Gene and Associated Diseases
Variants of HCFC1 lead to various neurological phenotypes. Mutation of HCFC1, either in cblX or related syndromes, is associated with severe neurological defects, intractable epilepsy, and neural development defects, including intellectual disability. Multiple SNPs within HCFC1 were identified, suggesting HCFC1 can be related to Meniere’s disease (MD) pathogenesis. The linkage disequilibrium between sequence variations in HCFC1 and MD predicts this gene may be involved in disease pathogenesis.
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Reference
- Michaud, J.; et al. HCFC1 is a common component of active human CpG-island promoters and coincides with ZNF143, THAP11, YY1, and GABP transcription factor occupancy. Genome research. 2013, 23(6): 907-916.
