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The kidneys
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Autosomal recessive polycystic kidney disease (ARPKD) is much less common but leads to renal failure in infancy or early childhood. ARPKD is caused by a genetic mutation in the PKHD1 gene, which encodes the protein fibrocystin. In ARPKD there is less severe renal enlargement and the cysts are limited to dilatation of the collecting ducts. Those patients who survive infancy develop hepatic fibrosis and, with age, the liver complications become more significant.
Cystic disease of the kidneys
Published in Brice Antao, S Irish Michael, Anthony Lander, S Rothenberg MD Steven, Succeeding in Paediatric Surgery Examinations, 2017
Antenatally diagnosed bilateral cystic kidneys, which are enlarged, is almost always ARPKD. The disease is transmitted in an autosomal recessive pattern and thereby has a risk of 1 in 4 children for the parents who are carriers of the defective gene. The genetic defect is on the short arm of chromosome 6, on PKHD1, a gene that encodes fibrocystin/polyductin, which play a crucial part in collecting-tubular and biliary development.
Choledochal Malformation
Published in John F. Pohl, Christopher Jolley, Daniel Gelfond, Pediatric Gastroenterology, 2014
There are two distinct variants of Type 5 (intrahepatic) CM. The least common is an isolated cystic dilatation, within the right lobe and is probably of congenital origin. Unless there is any obstruction to bile flow and/or stone formation, then a Type 5 CM can be simply observed. The more common type of Type 5 CM is usually termed Caroli syndrome and is one of the fibropolycystic diseases of the liver. Unlike all the other CM variants it has a clear genetic etiology and relationship with renal pathology. It is characterized by bilobar, multiple saccular dilatations of the bile ducts, and early-onset intrinsic liver fibrosis probably with normal intrabiliary pressure and no common channel (34.6). Mutations of the autosomally recessive PKHD1 gene are commonly identified with this type of CM and fibrocystin is its gene product.
Analysis of the mechanism underlying liver diseases using human induced pluripotent stem cells
Published in Immunological Medicine, 2019
We have recently reported on the pathological molecular mechanism of congenital hepatic fibrosis (CHF), which was clarified using genetically engineered human iPS cells. The pathological mechanism of CHF is quite different from that of liver cirrhosis owing to chronic hepatitis; hepatic fibrosis in CHF patients is prominent with nodular formation, but necroinflammatory changes of hepatocytes and the activation of hepatic stellate cells are not evident in the CHF liver [33]. The gene responsible for CHF is PKHD1 (polycystic kidney and hepatic disease 1), which encodes the fibrocystin protein localized in the primary cilia of cholangiocytes [34,35]. Animal models of CHF, such as gene-targeted Pkhd1 mutated mice, have been developed [36–39]; however, there are several phenotypic differences between human CHF and these animal models. Thus, a disease model using human cells is necessary to study CHF pathophysiology. It is difficult to clarify such mechanisms using an iPS cell model derived from CHF patients because of the numerous mutation patterns without specific correlations between genetic and phenotype variations in CHF patients. Furthermore, the complete functional loss of PKHD1 is lethal in the fetal period [40–42].
Renal ciliopathies: promising drug targets and prospects for clinical trials
Published in Expert Opinion on Therapeutic Targets, 2023
Laura Devlin, Praveen Dhondurao Sudhindar, John A. Sayer
ARPKD is most commonly caused by mutations in PKHD1 that encodes fibrocystin, which interacts with PC1 and PC2 within the primary cilia [50,70–72]. Fibrocystin is a key regulator of cell proliferation, apoptosis and polarization [73]. More recently, mutations in DZIP1L have been associated with ARPKD which develop KF later in life, although this accounts for less than 1% of individuals [74]. DZIP1L is believed to be involved in proper localization of PC1 and PC2. Biallelic mutations in TULP3 have also been shown to give a phenotype resembling ARPKD, with progressive fibrocystic liver and kidney disease, as well as polycystic kidney disease [75]. The encoded protein TULP3 acts as a critical adaptor protein for ciliary trafficking.
A shotgun proteomic approach reveals novel potential salivary protein biomarkers for asthma
Published in Journal of Asthma, 2022
Orapan Poachanukoon, Sittiruk Roytrakul, Sittichai Koontongkaew
Concerning fibrocystin, one study showed that it may participate in regulating mucocilliary sensing and transport within pulmonary airways (24). In addition, chronic lung disease was observed in 11% of surviving autosomal recessive polycystic kidney disease (ARPKD) patients, suggesting a direct role of fibrocystin in normal lung epithelial cell functions (25). Desmoglein-2 is a secreted intercellular desmosome junction protein that functions in cellular adhesion. This protein may be vital to maintaining the homeostatic barrier function of airway epithelia (26). It is suggested that the alteration of this protein may involve in asthma, where the barrier function of epithelium is intrinsically disrupted (27).