On this page
SKIV2L
SKI2 subunit of superkiller complex
SKIV2L is located on the short (p) arm of chromosome 6, at band 6p21.33. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 6 in the library →Available at Jeen Health
Clinical tests that include this
Overview
SKIV2L (SKI2 subunit of superkiller complex) is located on chromosome 6p21.33 and encodes a helicase protein that participates in RNA surveillance. The protein is thought to function as part of the SKI complex, which collaborates with the cytosolic exosome to recognise and degrade excess or malformed messenger RNA transcripts. This quality-control mechanism helps ensure cellular growth proceeds normally by preventing the accumulation of aberrant RNA species.
Pathogenic variants in SKIV2L are inherited in an autosomal recessive manner and cause trichohepatoenteric syndrome, a multisystem disorder primarily affecting the gastrointestinal tract, hair, and liver. The gene is included on several NHS Genomic Medicine Service panels focused on intestinal disorders, immunodeficiency, and metabolic conditions.
What the gene does
The SKIV2L protein is predicted to act as a helicase within the SKI complex, a group of proteins that support the cytosolic exosome in breaking down messenger RNA molecules. Helicases are enzymes that unwind nucleic acid structures using energy from ATP hydrolysis, allowing other proteins to access and process RNA or DNA substrates.
The cytosolic exosome recognises mRNA transcripts that are incorrectly processed, excessively abundant, or no longer required by the cell. By facilitating the degradation of these transcripts, the SKI complex and exosome together maintain appropriate levels of functional mRNA. This surveillance process is thought to be particularly important during periods of active cell growth and division, when cells produce large quantities of RNA and must rapidly adjust gene expression in response to developmental or environmental signals.
While the precise biochemical role of SKIV2L remains under investigation, comparative studies with homologous proteins in yeast and other model organisms suggest that it contributes to the unwinding step that precedes mRNA degradation, thereby enabling the exosome to access and dismantle target transcripts efficiently.
Video: Genetics 101
Chromosome location
SKIV2L is located on the short arm of chromosome 6 at position 6p21.33, within a gene-dense region of the human genome. The encoded protein comprises 1,246 amino acids. Specific exon structure and transcript variant data for SKIV2L have not been extensively characterised in public databases, though the gene is recognised to produce a functional full-length protein product in multiple human tissues.
Protein structure
The SKIV2L protein contains several functional domains characteristic of helicase enzymes. A helicase ATP-binding domain spans amino acids 319 to 475, providing the structural framework for binding and hydrolysing ATP to power the unwinding reaction. Within this region, the DEVH box motif (amino acids 423-426) represents a highly conserved sequence signature found in RNA helicases of the DEAD-box and related families.
A helicase C-terminal domain extends from amino acids 585 to 755, contributing additional structural elements required for substrate recognition and catalytic activity. The protein also includes a disordered region between amino acids 220 and 246, which may confer flexibility for protein-protein interactions or regulatory modifications. Together, these domains enable SKIV2L to bind RNA substrates, couple ATP hydrolysis to conformational changes, and collaborate with partner proteins in the SKI complex.
Key variants
At least nine pathogenic variants in SKIV2L have been reported in individuals with trichohepatoenteric syndrome. Most of these variants are predicted to eliminate functional protein production, either through premature stop codons, frameshift mutations, or deletions affecting critical helicase domains. Because the condition follows autosomal recessive inheritance, affected individuals typically carry two pathogenic variants (either two copies of the same variant or two different variants). Carrier individuals, with one pathogenic variant and one functional copy, generally do not experience symptoms.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Biallelic pathogenic variants in SKIV2L cause trichohepatoenteric syndrome, a rare multisystem disorder also known as syndromic diarrhoea. The condition typically presents in the first few months of life with intractable diarrhoea that persists despite dietary modifications. Affected children often exhibit growth delays, distinctive facial features (including a prominent forehead and wide-set eyes), and abnormal hair that may be woolly, brittle, or easily broken.
Liver disease is common, ranging from mild enzyme elevation to more significant hepatic dysfunction. Immune abnormalities have been reported in some individuals, potentially contributing to recurrent infections. The severity and specific combination of features can vary among affected individuals, even those carrying identical SKIV2L variants, suggesting that additional genetic or environmental factors may influence disease expression.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic SKIV2L variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
SKIV2L appears on multiple NHS Genomic Medicine Service gene panels, reflecting its relevance to paediatric gastrointestinal and metabolic conditions. The gene holds green (high-evidence) status on the Developmental Disorders Genotype to Phenotype (DDG2P) panel and several disorder-specific panels including Intestinal Failure or Congenital Diarrhoea (R331), Primary Immunodeficiency or Monogenic Inflammatory Bowel Disease (R15), and Likely Inborn Error of Metabolism (R98). It is also listed on the Fetal Anomalies panel (R21), Gastrointestinal Epithelial Barrier Disorders panel, and the Infantile Enterocolitis & Monogenic Inflammatory Bowel Disease panel, underscoring the broad phenotypic spectrum associated with pathogenic variants in this gene.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is trichohepatoenteric syndrome?
Trichohepatoenteric syndrome is a rare autosomal recessive disorder caused by biallelic SKIV2L variants, characterised by chronic diarrhoea beginning in infancy, distinctive hair and facial features, liver abnormalities, and growth delays. The condition affects multiple organ systems and typically requires ongoing medical management.
How is SKIV2L inherited?
SKIV2L-related conditions follow autosomal recessive inheritance. An affected individual inherits one pathogenic variant from each parent, who are typically unaffected carriers. When both parents are carriers, each pregnancy has a 25% chance of resulting in an affected child.
Why is SKIV2L included on NHS genomic medicine panels?
SKIV2L holds green (high-evidence) status on several NHS panels because pathogenic variants cause a clinically recognisable syndrome with early-onset gastrointestinal, metabolic, and immune features. Molecular diagnosis can guide clinical management and inform family planning for at-risk relatives.
References
- Fabre A, Martinez-Vinson C, Goulet O. Syndromic diarrhea/Tricho-hepato-enteric syndrome. Orphanet journal of rare diseases. 2013. PMID: 23302111
- Fabre A, Charroux B, Martinez-Vinson C. SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome. American journal of human genetics. 2012. PMID: 22444670
- van Dijk EL, Schilders G, Pruijn GJ. Human cell growth requires a functional cytoplasmic exosome, which is involved in various mRNA decay pathways. RNA (New York, N.Y.). 2007. PMID: 17545563