2. Academic Validation
  3. Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans

Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans

  • Hepatology. 2020 Jun;71(6):2067-2079. doi: 10.1002/hep.30982.
Ranad Shaheen # 1,  Saud Alsahli # 1,  Nour Ewida 1,  Fatema Alzahrani 1,  Hanan E Shamseldin 1,  Nisha Patel 1,  Awad Al Qahtani 2,  Homoud Alhebbi 2,  Amal Alhashem 3 4,  Tarfa Al-Sheddi 1,  Rana Alomar 1,  Eman Alobeid 1,  Mohamed Abouelhoda 1 5,  Dorota Monies 1 5,  Abdulrahman Al-Hussaini 6 7 8,  Muneerah A Alzouman 9,  Mohammad Shagrani 7 10,  Eissa Faqeih 6,  Fowzan S Alkuraya 1 4 5
Affiliations

Affiliations

  • 1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 2 Department of Pediatric Gastroenterology & Hepatologist, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
  • 3 Department of Pediatric, Prince Sultan Medical Military City, Riyadh, Saudi Arabia.
  • 4 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
  • 5 Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
  • 6 Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
  • 7 College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
  • 8 Prince Abdullah Bin Khaled Celiac Disease Research Chair, Department of Pediatrics, Faculty of Medicine, King Saud University, Riyadh, Saudi Arabia.
  • 9 Histopathology Division, Central Military Laboratory and Blood Bank, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
  • 10 King Faisal Specialist Hospital and Research Center, Organ Transplant Centre, Riyadh, Saudi Arabia.
  • # Contributed equally.
PMID: 31595528 DOI: 10.1002/hep.30982
Abstract

Background and aims: The clinical consequences of defective primary cilium (ciliopathies) are characterized by marked phenotypic and genetic heterogeneity. Although fibrocystic liver disease is an established ciliopathy phenotype, severe neonatal cholestasis is rarely recognized as such.

Approach and results: We describe seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one and necessitating liver transplant in two). Positional mapping revealed a single critical locus on chromosome 7. Whole-exome Sequencing revealed three different homozygous variants in Tetratricopeptide Repeat Domain 26 (TTC26) that fully segregated with the phenotype. TTC26 (intraflagellar transport [IFT] 56/DYF13) is an atypical component of IFT-B complex, and deficiency of its highly conserved orthologs has been consistently shown to cause defective ciliary function in several model organisms. We show that cilia in TTC26-mutated patient cells display variable length and impaired function, as indicated by dysregulated sonic Hedgehog signaling, abnormal staining for IFT-B components, and transcriptomic clustering with cells derived from individuals with closely related ciliopathies. We also demonstrate a strong expression of Ttc26 in the embryonic mouse liver in a pattern consistent with its proposed role in the normal development of the intrahepatic biliary system.

Conclusions: In addition to establishing a TTC26-related ciliopathy phenotype in humans, our results highlight the importance of considering ciliopathies in the differential diagnosis of severe neonatal cholestasis even in the absence of more typical features.

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