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Hepatology. 2019 Oct 8. doi: 10.1002/hep.30982. [Epub ahead of print]

Biallelic mutations in TTC26 (IFT56) cause severe biliary ciliopathy in humans.

Author information

1
Department of Genetics, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh, 11211, Saudi Arabia.
2
Qatar Biomedical Research Institute (QBRI), P.O. Box 34110, Doha, Qatar.
3
Department of Pediatric Gastroenterologist & Hepatologist, Prince Sultan Military Medical city, Riyadh, 11159, Saudi Arabia.
4
Department of Pediatric, Prince Sultan Medical Military City, Riyadh, 11159, Saudi Arabia.
5
Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh, 11533, Saudi Arabia.
6
Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, 12371, Saudi Arabia.
7
Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, P.O. Box 59046, Riyadh, 11525, Saudi Arabia.
8
College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh, 11533, Saudi Arabia.
9
Department of Liver and SB Transplant and Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia.

Abstract

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. 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 TTC26 that fully segregated with the phenotype. TTC26 (IFT56/DYF-13) 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 (SHH), 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. 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.

PMID:
31595528
DOI:
10.1002/hep.30982

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