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TTC37
SKI3 subunit of superkiller complex
TTC37 is located on the long (q) arm of chromosome 5, at band 5q15. Arm ratio per GRCh38 - banding schematic.
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Clinical tests that include this
Overview
TTC37 resides on chromosome 5q15 and encodes a 1564-amino acid protein originally termed thespin. Research suggests this protein functions as part of the SKI complex, a multiprotein assembly that collaborates with the cytosolic exosome to recognise and degrade excess or defective messenger RNA. Loss of TTC37 function disrupts RNA quality control mechanisms within cells, leading to accumulation of aberrant transcripts that may interfere with normal cellular processes. Pathogenic variants in TTC37 follow an autosomal recessive inheritance pattern and are recognised on multiple NHS Genomic Medicine Service panels for gastrointestinal and metabolic disorders.
Carriers of a single TTC37 variant typically remain unaffected, but when two carriers have children together, each child has a 25% chance of inheriting both variants and developing trichohepatoenteric syndrome. Understanding TTC37 status is particularly relevant for family planning decisions in populations where founder variants have been identified.
What the gene does
The TTC37 protein is hypothesised to serve as a structural component of the SKI complex, an assembly that works in concert with the cytosolic exosome to manage cellular RNA homeostasis. The cytosolic exosome represents a major degradation machinery for messenger RNA, targeting transcripts that are malformed, over-abundant, or no longer needed by the cell. Evidence from model organisms suggests that the SKI complex acts as an adaptor, guiding the exosome to specific RNA substrates and facilitating their efficient breakdown.
Without functional TTC37, cells may lose the ability to selectively eliminate defective RNA molecules, resulting in the persistence of transcripts that encode truncated or aberrant proteins. This disruption in RNA surveillance appears particularly critical in rapidly dividing tissues such as intestinal epithelium, where high rates of protein synthesis demand robust quality control systems. The protein's role in supporting cellular growth and differentiation may explain why TTC37 dysfunction disproportionately affects the gastrointestinal tract during early development.
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Chromosome location
TTC37 is located on the long arm of chromosome 5 at cytogenetic band 5q15. This chromosomal region spans several megabases and contains multiple genes involved in developmental and metabolic pathways. The genomic structure and exon-intron organisation of TTC37 have not been extensively characterised in public databases, though the coding sequence produces a transcript encoding 1564 amino acids.
Protein structure
The TTC37 protein comprises 1564 amino acids and contains an extensive array of tetratricopeptide repeat (TPR) motifs distributed across its length. Fifteen distinct TPR domains have been mapped: TPR 1 (amino acids 6-39), TPR 2 (amino acids 40-73), TPR 3 (amino acids 272-305), TPR 4 (amino acids 307-339), TPR 5 (amino acids 386-419), TPR 6 (amino acids 420-453), TPR 7 (amino acids 455-492), TPR 8 (amino acids 493-527), TPR 9 (amino acids 564-597), TPR 10 (amino acids 598-631), TPR 11 (amino acids 633-665), TPR 12 (amino acids 679-713), TPR 13 (amino acids 790-824), TPR 14 (amino acids 826-860), and TPR 15 (amino acids 861-894).
TPR motifs are structural elements that mediate protein-protein interactions, typically forming scaffolds that bring together multiple components of large complexes. The abundance of these repeats in TTC37 is consistent with its proposed role as an adaptor within the SKI complex, where it may coordinate interactions between the exosome and substrate RNA molecules or regulatory factors.
Key variants
Over 25 pathogenic variants in TTC37 have been reported in association with trichohepatoenteric syndrome, encompassing missense substitutions, nonsense mutations, and frameshift alterations. These variants are distributed throughout the gene and generally result in complete loss of protein function. The autosomal recessive nature of the disorder means that individuals must inherit two pathogenic variants to manifest clinical features. Carrier frequencies vary across populations, with certain founder mutations enriched in specific ethnic groups.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Biallelic pathogenic variants in TTC37 cause trichohepatoenteric syndrome, a rare multisystem disorder characterised by severe chronic diarrhoea beginning in infancy, distinctive hair abnormalities (often described as woolly or easily broken hair), characteristic facial features, and liver dysfunction. Affected individuals typically present with failure to thrive and growth retardation due to malabsorption. The gastrointestinal manifestations often prove refractory to standard nutritional interventions, and many patients require parenteral nutrition. Liver involvement ranges from mild enzyme elevation to progressive fibrosis, and some individuals exhibit immune dysregulation or developmental delay. The phenotypic spectrum reflects the critical role of RNA quality control in tissues with high metabolic demands.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic TTC37 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
TTC37 holds green (diagnostic-grade) status on multiple NHS Genomic Medicine Service gene panels, reflecting its established clinical validity. It appears on panels including Gastrointestinal Epithelial Barrier Disorders, Intestinal Failure or Congenital Diarrhoea (R331), Infantile Enterocolitis and Monogenic Inflammatory Bowel Disease, Primary Immunodeficiency or Monogenic Inflammatory Bowel Disease (R15), Intellectual Disability (R29), Likely Inborn Error of Metabolism (R98), and Undiagnosed Metabolic Disorders. The gene is also listed on the DDG2P panel and Fetal Anomalies panel (R21), indicating its relevance in prenatal and paediatric diagnostic settings. This broad panel representation underscores the multisystem nature of TTC37-related disease and supports testing in individuals with unexplained chronic diarrhoea, growth failure, or syndromic presentations involving gastrointestinal and hepatic features.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean to be a carrier of a TTC37 variant?
Carriers possess one pathogenic variant and one functional copy of TTC37, which is typically sufficient for normal RNA quality control. Carriers do not develop trichohepatoenteric syndrome but can pass the variant to their children.
How is trichohepatoenteric syndrome diagnosed?
Diagnosis combines clinical recognition of the characteristic features - chronic diarrhoea, distinctive hair, facial appearance, and liver involvement - with molecular genetic testing to identify biallelic TTC37 variants. Early identification supports appropriate nutritional management and genetic counselling for families.
Why is TTC37 included on so many NHS panels?
The multisystem nature of trichohepatoenteric syndrome means affected individuals may present to gastroenterology, hepatology, immunology, or metabolic services. Inclusion across panels ensures the gene is considered when patients exhibit relevant phenotypic features in any of these specialties.
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