Effects of specific mutations involved in the development of CHF, CD, and CS (IMAGE)

Xia & He Publishing Inc.

Effects of specific mutations involved in the development of CHF, CD, and CS

Caption

(1) Mutations in PKHD1 result in the synthesis of defective fibrocystin, activating the cAMP and NF-kB pathways. Activation of cAMP increases ß-catenin, stimulating the production of chemokines such as IL-ß and CXLC10, which activate the JAK/STAT pathway, causing intracellular signal transduction events and altering gene expression. NF-kB activates NLRP3, which binds to ASC, cleaving caspase 1 and inducing the maturation of pro-IL-1ß and further chemokine activation. Chemokines also stimulate macrophage recruitment, activating TGF-ß and stimulating myofibroblasts and extracellular matrix, causing hepatic fibrosis.7,8–10 (2) Cilia dysfunction can occur secondary to mutations in TMEM67 and ZFYVE19. TMEM67 encodes meckelin, a protein that acts as a barrier for the cilia, and ZKYVE19 regulates ciliogenesis.11–13 The disruption of the tubular architecture leads to ductal ectasia, predisposing to stagnant bile, stone formation, and cholangitis. Defective small interlobular bile ducts characterize CHF. On the other hand, CD is characterized by defective large intrahepatic bile ducts, and CS is the combination of CHF and CD.14 ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; ß-Cat, ß-catenin; CD, Caroli disease; CHF, congenital hepatic fibrosis; CS, Caroli syndrome; FPC, fibrocystin; IL, interleukin; JAK, janus kinase; LEF, lymphoid enhancer-binding factor; NK-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, nod-like receptor protein containing pyrin 3; PKA, protein kinase A; PKHD1, polycystic kidney and hepatic disease 1 gene; STAT, signal transducers and activators of transcription; TCF, T-cell factor; TGF-ß, transforming growth factor beta; TMEM67, the meckel syndrome protein meckelin; ZFYVE19, zinc finger FYVE-type containing 19. Adapted with permission from Fabris et al., Nature Rev Gastroenterol Hepatol, 2019.

Credit

Jasmine Tidwell

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