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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.
Mitochondrial Dysfunction in Chronic Kidney Disease
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Maria V. Irazabal, Alfonso Eirin
PKD is a group of monogenic disorders characterized by progressive development of tubular cysts, associated with enlargement of the kidneys and destruction of the renal parenchyma (Irazabal and Torres 2013). The most common forms of PKD constitute autosomal dominant PKD (ADPKD) and autosomal recessive PKD (ARPKD). ADPKD typically presents in adults and is caused most commonly by mutations in either PKD1 or PKD2 genes, whereas ARPKD primarily affects children and results from mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene (Irazabal and Torres 2013). Both ADPKD and ARPKD progress toward ESRD, requiring renal replacement therapy. Furthermore, these patients present with a myriad of extra-renal manifestations including cysts in other organs (liver, pancreas), congenital hepatic fibrosis (mainly ARPKD), intracranial aneurysms and abnormalities in the cardiovascular, gastrointestinal, and genitourinary systems.
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.
Clinical utility of chromosomal microarray analysis and whole exome sequencing in foetuses with oligohydramnios
Published in Annals of Medicine, 2023
Xiaomei Shi, Hongke Ding, Chen Li, Ling Liu, LiHua Yu, Juan Zhu, Jing Wu
We also identified a homozygous point variation c.199-10T > G in the SLC25A20 gene in case 4. Mutation of SLC25A20 is causative for Carnitine-acylcarnitine translocase deficiency (CACTD). Case 5 presented with oligohydramnios, hyperechogenic kidneys and enlarged kidneys. WES revealed a compound heterozygous mutation in PKHD1, a gene associated with PKD4. Case 6 had bilateral renal dysplasia and hypoplastic nasal bone in addition to oligohydramnios. WES revealed a compound heterozygous mutation in FRAS1. Mutations in the FRAS1 gene may cause Fraser syndrome. Case 7 carried a heterozygous mutation of (c.1406_1413dup8) in the HNF1B gene. Mutations in this gene cause renal cysts and diabetes syndrome. Ultrasound of this foetus showed severe oligohydramnios, bilateral renal dysplasia and an enlarged heart.
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].
New insights into targeting hepatic cystogenesis in autosomal dominant polycystic liver and kidney disease
Published in Expert Opinion on Therapeutic Targets, 2020
Thijs R. M. Barten, Lucas H. P. Bernts, Joost P. H. Drenth, Tom J. G. Gevers
This difference in phenotype could be explained by the function of these genes since the proteins encoded by DNAJB11, PRKCSH, SEC63, GANAB, ALG8, and SEC61B reside within the endoplasmic reticulum and are involved in maturation and trafficking of PC1. PKHD1 is not present in the endoplasmic reticulum biogenesis pathway, but instead encodes fibrocystin which is an integral membrane protein located in the primary cilium [18]. While fibrocystin has been associated with PC 1 and 2, its exact function remains uncertain [19].