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HCFC1
host cell factor C1
The HCFC1 gene encodes the Host Cell Factor C1 protein (HCF-1), a crucial transcriptional regulator involved in gene activity, vitamin B12 metabolism, and cell cycle progression. HCFC1 provides instructions for the HCF-1 protein, which plays a vital role in controlling the activity of numerous other genes.
HCFC1 is located on the long (q) arm of chromosome X, at band Xq28. Arm ratio per GRCh38 - banding schematic.
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Overview
The HCFC1 gene, also known as host cell factor C1, is responsible for producing the HCF-1 protein. This protein acts as a transcriptional regulator, meaning it helps control the expression levels of other genes throughout the body. Its functions are diverse, ranging from metabolic pathways to the regulation of cell proliferation and differentiation, particularly within the developing nervous system.
What the gene does
The HCF-1 protein, encoded by the HCFC1 gene, performs several critical functions by interacting with transcription factors to regulate gene activity. One key role involves regulating the MMACHC gene, which is essential for processing vitamin B12 (cobalamin). HCF-1 helps convert vitamin B12 into active forms, adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which are cofactors for enzymes like methylmalonyl CoA mutase and methionine synthase, respectively. These enzymes are crucial for breaking down certain amino acids, fatty acids, and for converting homocysteine to methionine. Beyond metabolism, HCF-1 also regulates genes involved in the cell cycle and is important for the proper distribution of cells during tissue and organ development, including brain development.
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Chromosome location
The HCFC1 gene is located on the long arm of the X chromosome at position 28, denoted as Xq28. This chromosomal location indicates that the gene follows an X-linked inheritance pattern, meaning that conditions associated with HCFC1 variants tend to affect males more severely due to having only one X chromosome.
Protein structure
The HCFC1 protein, HCF-1, is 2035 amino acids long and features several distinct domains and regions. It contains multiple Kelch repeats (Kelch 1, Kelch 2, Kelch 3, Kelch 4, Kelch 5) located between amino acids 44 and 313. A Fibronectin type-III 1 domain is present from amino acids 366-466, which includes a Disordered region from amino acids 407-434. Other key functional regions include one required for interaction with OGT (amino acids 500-550), an interaction with SIN3A region (amino acids 610-722), and interaction regions with ZBTB17 (amino acids 750-902) and GABP2 (amino acids 813-912). Additionally, the protein contains several HCF repeats, specifically HCF repeat 1 (amino acids 1010-1035), HCF repeat 2 (amino acids 1072-1097), HCF repeat 3 (amino acids 1101-1126), and a degenerate HCF repeat 4 (amino acids 1158-1183).
Key variants
Variants within the HCFC1 gene can lead to alterations in the structure or function of the HCF-1 protein. These genetic changes can impair the protein's ability to regulate other genes, process vitamin B12, or participate in cell cycle control and development. The specific impact of a variant often depends on its location and the resulting effect on the protein's overall function.
Sample of pathogenic variants
8 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.344C>T | p.Ala115Val | Pathogenic | ★★☆☆ | Methylmalonic acidemia with homocystinuria, type cblX |
c.1367dup | p.Thr457fs | Pathogenic | ★☆☆☆ | Inborn genetic diseases |
c.5048C>G | p.Pro1683Arg | Pathogenic | ★☆☆☆ | Methylmalonic acidemia with homocystinuria, type cblX |
c.5860G>A | p.Gly1954Arg | Pathogenic | ★☆☆☆ | Inborn genetic diseases |
c.6046C>T | p.Arg2016Trp | Pathogenic | ★☆☆☆ | not provided |
c.217G>A | p.Ala73Thr | Pathogenic | - | Methylmalonic acidemia with homocystinuria, type cblX |
c.674G>A | p.Ser225Asn | Pathogenic | - | Methylmalonic acidemia with homocystinuria, type cblX |
c.-970T>C | - | Pathogenic | - | Methylmalonic acidemia with homocystinuria, type cblX |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the HCFC1 gene are associated with various neurodevelopmental and metabolic disorders. These include methylmalonic acidaemia with homocystinuria, cblX type, which presents with developmental delay, neurological issues, eye defects, blood abnormalities, and severe craniofacial anomalies. Other individuals with HCFC1 variants may experience X-linked intellectual disability and delayed development without the additional metabolic features of cblX type.
No disease links recorded for this gene in our reference set.
UK clinical status
The HCFC1 gene is part of several NHS Genomic Medicine Service clinical panels, indicating its clinical significance in the UK. It is included in the green listed sections for DDG2P, Dystonia, chorea or related movement disorder (childhood onset, R57), Early onset or syndromic epilepsy, Foetal anomalies (R21), Intellectual disability, Likely inborn error of metabolism (R98), and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the HCFC1 gene?
The HCFC1 gene provides instructions for making the HCF-1 protein, which is a key regulator of other genes. It is involved in essential processes like vitamin B12 metabolism, cell cycle regulation, and cellular distribution during development.
What conditions are associated with HCFC1 gene variants?
Variants in the HCFC1 gene are linked to methylmalonic acidaemia with homocystinuria, cblX type, which causes developmental and neurological problems, and X-linked intellectual disability.
Why is HCFC1 important for vitamin B12 metabolism?
HCFC1 helps regulate the MMACHC gene, which is critical for converting vitamin B12 into its active forms. These active forms are cofactors for enzymes that break down specific amino acids and fatty acids, and convert homocysteine to methionine.
References
- Gérard M, Morin G, Bourillon A. Multiple congenital anomalies in two boys with mutation in HCFC1 and cobalamin disorder. European journal of medical genetics. 2015. PMID: 25595573
- Jolly LA, Nguyen LS, Domingo D. HCFC1 loss-of-function mutations disrupt neuronal and neural progenitor cells of the developing brain. Human molecular genetics. 2015. PMID: 25740848
- Parker JB, Yin H, Vinckevicius A. Host cell factor-1 recruitment to E2F-bound and cell-cycle-control genes is mediated by THAP11 and ZNF143. Cell reports. 2014. PMID: 25437553
- Yu HC, Sloan JL, Scharer G. An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1. American journal of human genetics. 2013. PMID: 24011988
- Zargar Z, Tyagi S. Role of host cell factor-1 in cell cycle regulation. Transcription. 2012. PMID: 22771988
- Huang L, Jolly LA, Willis-Owen S. A noncoding, regulatory mutation implicates HCFC1 in nonsyndromic intellectual disability. American journal of human genetics. 2012. PMID: 23000143