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Heterozygosity for human polycystic kidney and hepatic disease 1 ( PKHD1) mutations was recently associated with cystic liver disease and radiographic findings resembling medullary sponge kidney (MSK). However, the relevance of these associations has been tempered by a lack of cystic liver or renal disease in heterozygous mice carrying Pkhd1 gene trap or exon deletions. To determine whether heterozygosity for a smaller Pkhd1 defect can trigger cystic renal disease in mice, we generated and characterized mice with the predicted truncating Pkhd1 C642* mutation in a region corresponding to the middle of exon 20 cluster of five truncating human mutations (between PKHD1 G617fs and PKHD1 G644* ). Mouse heterozygotes or homozygotes for the Pkhd1 C642* mutation did not have noticeable liver or renal abnormalities on magnetic resonance images during their first weeks of life. However, when aged to ~1.5 yr, the Pkhd1 C642* heterozygotes developed prominent cystic liver changes; tissue analyses revealed biliary cysts and increased number of bile ducts without signs of congenital hepatic fibrosis-like portal field inflammation and fibrosis that was seen in Pkhd1 C642* homozygotes. Interestingly, aged female Pkhd1 C642* heterozygotes, as well as homozygotes, developed radiographic changes resembling MSK. However, these changes correspond to proximal tubule ectasia, not an MSK-associated collecting duct ectasia. In summary, by demonstrating that cystic liver and kidney abnormalities are triggered by heterozygosity for the Pkhd1 C642* mutation, we provide important validation for relevant human association studies. Together, these investigations indicate that PKHD1 mutation heterozygosity (predicted frequency 1 in 70 individuals) is an important underlying cause of cystic liver disorders and MSK-like manifestations in a human population.

Rare kidney diseases encompass at least 150 different conditions, most of which are inherited. Although individual rare kidney diseases raise specific issues, as a group these rare diseases can have overlapping challenges in diagnosis and treatment. These challenges include small numbers of affected patients, unidentified causes of disease, lack of biomarkers for monitoring disease progression, and need for complex care. To address common clinical and patient issues among rare kidney diseases, the KDIGO Controversies Conference entitled, Common Elements in Rare Kidney Diseases, brought together a panel of multidisciplinary clinical providers and patient advocates to address five central issues for rare kidney diseases. These issues encompassed diagnostic challenges, management of kidney functional decline and progression of chronic kidney disease, challenges in clinical study design, translation of advances in research to clinical care, and provision of practical and integrated patient support. Thus, by a process of consensus, guidance for addressing these challenges was developed and is presented here., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Nephronophthisis-related ciliopathies (NPHP-RC) are recessive disorders that feature dysplasia or degeneration occurring preferentially in the kidney, retina and cerebellum. Here we combined homozygosity mapping with candidate gene analysis by performing 'ciliopathy candidate exome capture' followed by massively parallel sequencing. We identified 12 different truncating mutations of SDCCAG8 (serologically defined colon cancer antigen 8, also known as CCCAP) in 10 families affected by NPHP-RC. We show that SDCCAG8 is localized at both centrioles and interacts directly with OFD1 (oral-facial-digital syndrome 1), which is associated with NPHP-RC. Depletion of sdccag8 causes kidney cysts and a body axis defect in zebrafish and induces cell polarity defects in three-dimensional renal cell cultures. This work identifies loss of SDCCAG8 function as a cause of a retinal-renal ciliopathy and validates exome capture analysis for broadly heterogeneous single-gene disorders.

With the completion of the Human Genome Project and the associated advances in genomic technologies, clinicians have at their disposal an increasing repertoire of tools to provide accurate and efficient diagnosis, assess disease predisposition and risk factors, and personalize therapeutic management. To date, more than 2,000 human disease genes have been identified, including genes involved in single-gene disorders that disrupt the structure and/or function of the kidney and developing urinary tract. The use of genetic tests for diagnostic purposes increasingly is being integrated into general medical practice and therefore it is important for clinicians to be familiar with the technical approaches and ethical implications of these methods. Here, we provide an overview of the utility and limitations of current genetic tests for diagnosis, prenatal examination, carrier detection, and presymptomatic testing of hereditary disorders, with emphasis on pediatric renal disorders. In addition, we describe new technical advances that are expected to be introduced into clinical practice in the coming years.

Heterozygosity for human polycystic kidney and hepatic disease 1 (PKHD1) mutations was recently associated with cystic liver disease and radiographic findings resembling medullary sponge kidney (MSK). However, the relevance of these associations has been tempered by a lack of cystic liver or renal disease in heterozygous mice carrying Pkhd1 gene trap or exon deletions. To determine whether heterozygosity for a smaller Pkhd1 defect can trigger cystic renal disease in mice, we generated and characterized mice with the predicted truncating Pkhd1C642** mutation in a region corresponding to the middle of exon 20 cluster of five truncating human mutations (between PKHD1G617fs and PKHD1G644*). Mouse heterozygotes or homozygotes for the Pkhd1C642** mutation did not have noticeable liver or renal abnormalities on magnetic resonance images during their first weeks of life. However, when aged to ~1.5 yr, the Pkhd1C642** heterozygotes developed prominent cystic liver changes; tissue analyses revealed biliary cysts and increased number of bile ducts without signs of congenital hepatic fibrosis-like portal field inflammation and fibrosis that was seen in Pkhd1C642** homozygotes. Interestingly, aged female Pkhd1C642** heterozygotes, as well as homozygotes, developed radiographic changes resembling MSK. However, these changes correspond to proximal tubule ectasia, not an MSK-associated collecting duct ectasia. In summary, by demonstrating that cystic liver and kidney abnormalities are triggered by heterozygosity for the Pkhd1C642** mutation, we provide important validation for relevant human association studies. Together, these investigations indicate that PKHD1 mutation heterozygosity (predicted frequency 1 in 70 individuals) is an important underlying cause of cystic liver disorders and MSK-like manifestations in a human population. [ABSTRACT FROM AUTHOR]

Inherited renal cystic diseases constitute an important set of single-gene disorders that frequently progress to end stage renal disease (ESRD). Transmitted as autosomal dominant, autosomal recessive, or X-linked traits, renal cystic diseases are phenotypically diverse with respect to age at onset, rate of disease progression, and associated extra-renal manifestations. These disorders involve defects in a set of gene products commonly referred to as cystoproteins that, while functionally distinct, appear to co-localize, at least in part, with the cilia/centrosome complex. Therefore, investigations are increasingly focused on the role of this complex in the pathogenesis of renal cystic disease. Sorting out the functional relationship between these cystoproteins and the cilia/centrosome complex will undoubtedly provide a better understanding of renal cystic disease pathogenesis and, potentially, identify new targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by dilation of ectatic renal collecting ducts, intrahepatic biliary dysgenesis, and portal fibrosis. Portal hypertension and recurrent bacterial cholangitis can dominate the clinical picture in long-term survivors. Predominant extrahepatic bile duct disease was revealed in four patients who underwent magnetic resonance cholangiopancreatography. All four patients had portal hypertension, although liver biochemistries did not suggest biliary disease. In two of the patients, cholangitis was clinically ascribed to the bile duct disease. Western blot analysis of plasma membranes from normal rat extrahepatic bile duct and kidney revealed the presence of polyductin as a single ∼440 kDa protein. Although the exact function of polyductin in the extrahepatic duct is unknown, it may have a role in the development and control of lumenal size. Clinical management of patients with ARPKD should include consideration of potential problems related to extrahepatic bile duct disease. [ABSTRACT FROM AUTHOR]

Numerous murine (mouse and rat) models of polycystic kidney disease (PKD) have been described in which the mutant phenotype results from a spontaneous mutation or engineering via chemical mutagenesis, transgenic technologies, or gene-specific targeting in mouse orthologs of human PKD genes. These murine phenotypes closely resemble human PKD, with common abnormalities observed in tubular epithelia, the interstitial compartment, and the extracellular matrix of cystic kidneys. In both human and murine PKD, genetic background appears to modulate the renal cystic phenotype. In murine models, these putative modifying effects have been dissected into discrete factors called quantitative trait loci and genetically mapped. Several lines of experimental evidence support the hypothesis that PKD genes and their modifiers may define pathways involved in cystogenesis and PKD progression. Among the various pathway abnormalities described in murine PKD, recent provocative data indicate that structural and/or functional defects in the primary apical cilia of tubular epithelia may play a key role in PKD pathogenesis. This review describes the most widely studied murine models; highlights the data regarding specific gene defects and genetic modifiers; summarizes the data from these models that have advanced our understanding of PKD pathogenesis; and examines the effect of various therapeutic interventions in murine PKD. [ABSTRACT FROM AUTHOR]

By positional cloning techniques, we have identified the gene that is disrupted in the jcpk and bpk mouse models for polycystic kidney disease. This gene is the mouse homolog of the Drosophila Bicaudal C gene. Both of these mutations have been mapped to a very short stretch of Chromosome (Chr) 10. By sequencing the bicaudal C gene, Bicc1, in these models, it was found that the jcpk mutation results in a shortened and abnormal transcript, whereas the bpk mutation results in an abnormal 3′ coding region. In Drosophila, this gene encodes a protein known to influence developmental processes. The mammalian homolog contains three KH (K homology) domains and a SAM (sterile alpha motif) domain and is expressed in the developing embryo, indicating that it may be important in RNA-binding and/or protein interactions during embryogenesis. [ABSTRACT FROM AUTHOR]

The article presents the consensus reached at first NIH/Office of Rare Diseases Conference on cystinosis, which was held on May 12-13, 2004. The meeting addressed the past, present, and future of nephropathic cystinosis research. In this meeting there was agreement on the importance of several topics related to the disease like early diagnosis of cystinosis, efficiency of treatment, oral cysteamine therapy, role of pediatric nephrologists, etc. It was finally concluded that future studies should include investigations into the value of therapies to reduce proteinuria.

Editorial. Focuses on phenotypic variability in polycystic kidney disease (PKD). Characteristics of the disease; Progression of renal cystic lesion; Clinical expression of PKD1-related diseases.

A letter to the editor is presented in response to the article related with renal macrophages in autosomal recessive polycystic kidney disease.

Discusses genetic disorders of renal electrolyte transport. Mutations affecting the epithelial sodium channel; Renal tubular disorders inherited by mendelian traits; Mutations affecting diuretic-sensitive sodium-transport proteins; Mutations associated with X-linked hypophoshatemic rickets; Conclusions.

Monocyte and macrophage markers are among the most highly overexpressed genes in cpk mouse kidneys with severely progressive renal cystic disease. We show here that one of these markers, CD14, is abnormally transcribed, activated and shed in cystic kidneys. However, these abnormalities were not associated with an increased number of interstitial CD14-positive mononuclear cells. Instead, we found that most non-cystic and cystic renal tubular epithelia were CD14-positive; even distal nephron-derived principal cells. Cd14 was significantly overexpressed in the kidneys of 5-day-old cpk mice and further increased as the disease progressed. In the cpk model with variable rates of cystic kidney enlargement (due to an intercross of two distinct genetic backgrounds), Cd14 expression positively correlated with kidney volume, exceeding the correlation with MCP-1, an established marker of autosomal-dominant polycystic kidney disease (ADPKD). In 16 patients with ADPKD, the baseline urinary CD14 level showed some tendency to correlate with the 2-year change in total kidney volume; however, the tendency was not statistically significant. But the association was significant when the analysis was confined to males. Clearly more studies need to be done to evaluate the utility of CD14 as a marker for outcomes in ADPKD. [ABSTRACT FROM AUTHOR]

Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome. Gitelman syndrome (familial hypokalemia-hypomagnesemia syndrome) is an autosomal recessive inherited renal disorder characterized by defective tubular reabsorption of magnesium and potassium. In this study a group of 18 unrelated and 2 related Gitelman patients, collected from six different countries have been screened for mutations in the human thiazide-sensitive sodium-chloride cotransporter (SLC12A3) gene. Fourteen novel SLC12A3 mutations are presented along with six mutations described earlier, and three neutral polymorphisms. Among the tested patients are two who carry a total of three heterozygous SLC12A3 mutations. Two-thirds of the total number of mutant SLC12A3 alleles are amino acid substitutions. Most SLC12A3 gene mutations, 14 out of a total of 20, are localized at the intracellular carboxy-terminal domain of the NCCT protein. The pathogenicity of individual SLC12A3 mutations is based upon their predicted effect on SLC12A3 protein, and segregation in family members. Evolutionary conservation of substituted amino acid residues and their frequency in control chromosomes is presented. Identical mutations have been found in Gitelman families from different geographical origin, suggesting ancient mutations originating from a common ancestor. As yet, we have not found any evidence for a possible genotype-phenotype correlation. [ABSTRACT FROM AUTHOR]

The article presents information on a study conducted on a family with congenital nephrogenic diabetes insipidus, a rare hereditary disorder in which renal responsiveness to arginine vasopressin is impaired. Study conducted on three second-generation male subjects of the family, showed that they had severe polydipsia and polyuria. The study showed that the three affected second-generation family members have continued to have polydipsia and polyuria as adults. The study also showed that the male family members in the third generation were affected in the same way as those in the second generation.