Autosomal Recessive Kidney Disease Research Articles

The Pathophysiology of Inherited Renal Cystic Diseases.

Renal cystic diseases (RCDs) can arise from utero to early adulthood and present with a variety of symptoms including renal, hepatic, and cardiovascular manifestations. It is well known that common RCDs such as autosomal polycystic kidney disease and autosomal recessive kidney disease are linked to genes such as PKD1 and PKHD1, respectively. However, it is important to investigate the genetic pathophysiology of how these gene mutations lead to clinical symptoms and include some of the less-studied RCDs, such as autosomal dominant tubulointerstitial kidney disease, multicystic dysplastic kidney, Zellweger syndrome, calyceal diverticula, and more. We plan to take a thorough look into the genetic involvement and clinical sequalae of a number of RCDs with the goal of helping to guide diagnosis, counseling, and treatment.

Clinical features and gene variation analysis of COQ8B nephropathy: Report of seven cases.

COQ8B nephropathy is a relatively rare autosomal recessive kidney disease characterized by proteinuria and a progressive deterioration of renal function, eventually leading to end-stage renal disease (ESRD). The objective is to study the characteristics and correlation between the genotype and the clinical phenotype of COQ8B nephropathy. This is a retrospective study focusing on the clinical characteristics of seven COQ8B nephropathy patients diagnosed by gene sequencing. Basic clinical information, clinical manifestations, examinations, imaging, genomes, pathology, treatments, and prognosis of the patients were reviewed. Of the seven patients, two were male children and five were female children. The median age at the disease onset was 5 years and 3 months. The initial main clinical manifestations were proteinuria and renal insufficiency. Four patients had severe proteinuria, four had focal segmental glomerulosclerosis (FSGS) diagnosed by a renal biopsy, and two had nephrocalcinosis after an ultrasound was performed on them. There were no other clinical manifestations such as neuropathy, muscle atrophy, and so on in all of them. Their gene mutations were all exon variants, which were classified as heterozygous or homozygous variants by performing family verification analysis. Compound heterozygous variants were predominant in all, and all gene variants were inherited from their parents. One novel mutation, c.1465c>t, was found in this study. This gene mutation resulted from changes in the amino acid sequence, thus leading to an abnormal protein structure. Two patients with early diagnosis of COQ8B nephropathy presented with no renal insufficiency and were treated with oral coenzyme Q10 (CoQ10), and they maintained normal renal function. For the remaining five who were treated with CoQ10 following renal insufficiency, the deterioration of renal function could not be reversed, and they progressed to ESRD within a short time (median time: 7 months). A follow-up of these patients showed normal renal function with a CoQ10 supplement. For unexplained proteinuria, renal insufficiency, or steroid-resistant nephrotic syndrome, gene sequencing should be considered, in addition to renal biopsy, as early as possible. Timely diagnosis of COQ8B nephropathy and early supplementation of sufficient CoQ10 can help control the progression of the disease and significantly improve the prognosis.

Hipokalemija - rani marker autozomno recesivne tubulopatije (Gitelmanov sindrom) - prikaz slučaja

Hypokalemia is the most common feature of Gitelman syndrome, which is a rare, inherited, autosomal recessive kidney disease associated with tubule disease. In addition to hypokalemia, it is also characterized by hypomagnesemia, metabolic alkalosis, hyperrenemic hyperaldosteronism, normal or lower blood pressure, while the presence of arterial hypertension does not exclude the diagnosis. It affects men and women equally, with a prevalence of 1 to 10 cases per 40,000 inhabitants. The most common cause are mutations in the SLC12A3 gene, which encodes the thiazidesensitive sodium chloride cotransporter (NCCT) in the renal distal tubules, and the TRPM6 (cation channel subfamily 6 protein claudin 16) gene, which controls distal tubular magnesium transport. The aim of the paper is to present an adult patient with pronounced hypokalemia as part of Gitelman's syndrome. Case report: We present a 21-year-old man with severe hypokalemia as part of Gitelman's syndrome. The disease manifested itself in non-specific complaints, and laboratory findings showed hypokalemia of 2.0 mmol/L, which was the reason for urgent hospitalization. Further examinations of the patient verified the following: hypomagnesemia, hypocalciuria, metabolic alkalosis, preserved kidney function and arterial hypotension. Other potential causes of hypokalemia were excluded by differential diagnosis. He was treated with potassium and magnesium replacement therapy, after which the symptoms of hypokalemia disappeared, and the electrolyte values were closer to the reference values. The diagnosis of Gitelman's syndrome was made based on clinical and laboratory findings. A geneticist was also consulted. Hypokalemia as part of Gitelman's syndrome is rarely encountered in clinical practice, and it is rarely thought of. Severe forms of hypokalemia should arouse suspicion of its existence and lead to a final diagnosis, for which rich clinical experience and teamwork are necessary. The patients with symptoms should be treated symptomatically, and those without symptoms should be monitored 1-2 times a year.

Comprehensive genetic analysis using next-generation sequencing for the diagnosis of nephronophthisis-related ciliopathies in the Japanese population.

Nephronophthisis is an autosomal-recessive kidney disease that is caused by abnormalities in primary cilia. Nephronophthisis-related ciliopathies (NPHP-RCs) are a common cause of end-stage kidney disease (ESKD) in children and adolescents. NPHP-RCs are often accompanied by extrarenal manifestations, including intellectual disability, retinitis pigmentosa, or polydactyly. Although more than 100 causative genes have been identified, its diagnosis is difficult because the clinical features of each mutation often overlap. From September 2010 to August 2021, we performed genetic analysis, including next-generation sequencing (NGS), in 574 probands with kidney dysfunction and retrospectively studied cases genetically diagnosed with NPHP-RCs. RESULTS: We detected mutations related to NPHP-RCs in 93 patients from 83 families. Members of 60 families were diagnosed using NGS, and the mutations and the corresponding number of families are as follows: NPHP1 (24), NPHP3 (10), OFD1 (7), WDR35 (5), SDCCAG8 (4), BBS10 (3), TMEM67 (3), WDR19 (3), BBS1 (2), BBS2 (2), IFT122 (2), IFT140 (2), IQCB1 (2), MKKS (2), SCLT1 (2), TTC21B (2), ALMS1 (1), ANKS6 (1), BBS4 (1), BBS12 (1), CC2D2A (1), DYNC2H1 (1), IFT172 (1), and MAPKBP1 (1). A total of 39 cases (41.9%) progressed to ESKD at the time of genetic analysis, whereas 58 cases (62.3%) showed extrarenal manifestations, the most common being developmental delay, intellectual disability, and autism spectrum disorder in 44 patients. Comprehensive genetic analysis using NGS is useful for diagnosing patients with NPHP-RCs.

Multicystic dysplastic kidney

Multicystic dysplastic kidney

MO049FUNCTIONAL IMPORTANCE OF MAPKBP1 PROTEIN DOMAINS IN NEPHRONOPHTHISIS

Abstract Background and Aims Nephronophthisis is an autosomal-recessive kidney disease that accounts for a significant proportion of end-stage renal disease (ESRD) in childhood, adolescence and early adulthood. Biallelic pathogenic variants in MAPKBP1, encoding the c-Jun N-terminale kinase (JNK)-binding protein 1, are associated with development of Nephronophthisis and subsequent chronic kidney disease (CKD) (Macia et al, AJHG, 2017). We recently characterized MAPKBP1 as microtubule-associated protein that is able to localize to centrioles and the base of primary cilia depending on dimerization via its C-terminal coiled-coil domain (Schönauer et al, Kidney Int, 2020). However, the physiological function of its N-terminal WD40 and intermediate JNK-binding domain is still poorly understood. By in vitro comparison of artificial domain deletions with known and novel patient variants, we aim at pinpointing functional consequences of pathogenic MAPKBP1 in cilia and cell cycle control. Method N-terminally GFP-tagged MAPKBP1 constructs with either full-domain deletions or patient-derived variants were expressed in non-ciliated HeLa and ciliated H69 cells for fluorescence microscopy studies. Furthermore, RNA-seq analysis using primary patient cells was conducted to investigate differentially regulated molecular pathways compared to healthy control individuals. Results Immunofluorescence microscopy revealed inappropriate intracellular localization upon single or combined deletion of any MAPKBP1 protein domain. Compared to wild type, all deletion variants showed reduced intensity at the centrosome and ciliary base. Despite preserved dimerization ability, loss of the intermediate JNK-binding domain (JBD) most effectively abolished centrosomal or ciliary targeting, whereas loss of the N-terminal WD40-domain induced strongest mitotic aberrations. Unlike wild type, both, artificial and patient-derived truncating variants were able to enter the nucleus. RNA-seq analysis using primary patient fibroblasts with varying C-terminal truncations will allow important insights into common gene expression profiles unveiling consequences of aberrant intracellular trafficking. Conclusion In the present work, we demonstrate that all protein domains are indispensable for appropriate MAPKBP1 intracellular localization and function. Most of clinically reported patient variants exhibiting C-terminal truncation of varying lengths resulted in comparable intracellular behavior in presence of an intact N-terminal WD40 domain. Surprisingly, deletion of the JNK-binding domain alone aggravated functional disturbances hinting at a prominent regulatory role of this protein part interdepending with dimerization. Further insights into domain-specific functions will explain molecular disease mechanisms of MAPKBP1.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC; OMIM 248250) is a rare autosomal recessive kidney disease caused by mutations in the CLDN16 or CLDN19 genes encoding the proteins claudin-16 and claudin-19, respectively. These are involved in paracellular magnesium and calcium transport in the thick ascending limb of Henle's loop and account for most of the magnesium reabsorption in the tubules. FHHNC is characterized by hypomagnesaemia, hypercalciuria, and nephrocalcinosis, and progresses to kidney failure, requiring dialysis and kidney transplantation mainly during the second to third decades of life. Patients carrying CLDN19 mutations frequently exhibit associated congenital ocular defects leading to variable visual impairment. Despite this severe clinical course, phenotype variability even among siblings has been described in this disease, suggesting unidentified epigenetic mechanisms or other genetic or environmental modifiers. Currently, there is no specific therapy for FHHNC. Supportive treatment with high fluid intake and dietary restrictions, as well as magnesium salts, thiazides, and citrate, are commonly used in an attempt to retard the progression of kidney failure. A kidney transplant remains the only curative option for kidney failure in these patients. In this review, we summarize the current knowledge about FHHNC and discuss the remaining open questions about this disorder.

Roscovitine blocks collecting duct cyst growth in Cep164-deficient kidneys

Nephronophthisis is an autosomal recessive kidney disease with high genetic heterogeneity. Understanding the functions of the individual genes contributing to this disease is critical for delineating the pathomechanisms of this disorder. Here, we investigated kidney function of a novel gene associated with nephronophthisis, CEP164, coding a centriolar distal appendage protein, using a Cep164 knockout mouse model. Collecting duct-specific deletion of Cep164 abolished primary cilia from the collecting duct epithelium and led to rapid postnatal cyst growth in the kidneys. Cell cycle and biochemical studies revealed that tubular hyperproliferation is the primary mechanism that drives cystogenesis in the kidneys of these mice. Administration of roscovitine, a cell cycle inhibitor, blocked cyst growth in the cortical collecting ducts and preserved kidney parenchyma in Cep164 knockout mice. Thus, our findings provide evidence that therapeutic modulation of cell cycle activity can be an effective approach to prevent cyst progression in the kidney.

Progress in genetics of NPHP related signaling pathway

Nephronophthisis(NPHP), an autosomal recessive cystic kidney disease, is the most frequent genetic cause for end stage renal failure in the first thirty years of life.NPHP can be caused by Mutations in 22 genes(NPHP1-20, NPHPL1, NPHPL2), with abnormal structure or function of primary cilia, involved in Hh, Wnt, Hippo, DDR signaling pathways.Elucidating the pathogenic genes and possible pathogenesis would make a difference in prevention, diagnosis, treatment, prognosis, and genetic counseling of NPHP.This article reviews the pathogenic genetics and related signaling pathways. Key words: Nephronophthisis; Hh signal pathway; Wnt signal pathway; Hippo signal pathway; DDR signal pathway

Polycystic kidney and hepaticdisease 1 mutations lead to childhood autosomal recessive polycystic kidney disease with Carolis disease in 1 case and literature review

Polycystic kidney and hepaticdisease 1 mutations lead to childhood autosomal recessive polycystic kidney disease with Carolis disease in 1 case and literature review

Juvenile nephronophthisis and dysthyroidism: a rare association.

Nephronophthisis, an autosomal recessive kidney disease, represents the most frequent genetic cause of end-stage kidney disease in the first three decades of life. A 27-year-old male was presented with gait imbalance, sever pruritus since 10days prior time of admission. In past medical history, he had bilateral cataract, torsional nystagmus, and bilateral optic nerve atrophy since 2years of age. He was also mentioned history of multinodular goiter with dysfunctional thyroid state since 2years before admission. At admission bilateral blindness, torsional nystagmus, asymmetric thyromegaly with nodularity was found in physical examination. Laboratory tests showed elevated urea and creatinine (200, 10.7mg/dl), hypomagnesemia (1.1mEq/l), decreased thyroid stimulating hormone (<0.004mIU/l). Ophthalmologist consultation confirmed retinitis pigmentosa. Renal sonography showed small-sized kidneys. Brain magnetic resonance imaging did not reveal molar tooth sign. Genetic testing performed and a large homozygous deletion at the NPHP1 gene locus was found. The patient was diagnosed with juvenile nephronophthisis and consideration of dysthyroidism as extrarenal manifestation of nephronophthisis is suggested in this case. Furthermore, loss of function mutation in SLC41A1 gene that leads to magnesium depletion must be noted in patients with suspected to nephronophthisis.

How Does Autosomal Recessive Polycystic Kidney Disease Progress to Kidney Failure

Autosomal recessive polycystic kidney disease (ARPKD) can cause death in the neonatal period; however, the majority of children with this condition now

Gene diagnosis and clinical characteristics of autosomal recessive polycystic kidney disease

Gene diagnosis and clinical characteristics of autosomal recessive polycystic kidney disease

NPHP4 is necessary for normal photoreceptor ribbon synapse maintenance and outer segment formation, and for sperm development

Nephronophthisis (NPHP) is an autosomal recessive kidney disease that is often associated with vision and/or brain defects. To date, 11 genes are known to cause NPHP. The gene products, while structurally unrelated, all localize to cilia or centrosomes. Although mouse models of NPHP are available for 9 of the 11 genes, none has been described for nephronophthisis 4 (Nphp4). Here we report a novel, chemically induced mutant, nmf192, that bears a nonsense mutation in exon 4 of Nphp4. Homozygous mutant Nphp4(nmf192/nmf192) mice do not exhibit renal defects, phenotypes observed in human patients bearing mutations in NPHP4, but they do develop severe photoreceptor degeneration and extinguished rod and cone ERG responses by 9 weeks of age. Photoreceptor outer segments (OS) fail to develop properly, and some OS markers mislocalize to the inner segments and outer nuclear layer in the Nphp4(nmf192/nmf192) mutant retina. Despite NPHP4 localization to the transition zone in the connecting cilia (CC), the CC appear to be normal in structure and ciliary transport function is partially retained. Likewise, synaptic ribbons develop normally but then rapidly degenerate by P14. Finally, Nphp4(nmf192/nmf192) male mutants are sterile and show reduced sperm motility and epididymal sperm counts. Although Nphp4(nmf192/nmf192) mice fail to recapitulate the kidney phenotype of NPHP, they will provide a valuable tool to further elucidate how NPHP4 functions in the retina and male reproductive organs.

Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy

The autosomal recessive kidney disease nephronophthisis (NPHP) constitutes the most frequent genetic cause of terminal renal failure in the first 3 decades of life. Ten causative genes (NPHP1-NPHP9 and NPHP11), whose products localize to the primary cilia-centrosome complex, support the unifying concept that cystic kidney diseases are "ciliopathies". Using genome-wide homozygosity mapping, we report here what we believe to be a new locus (NPHP-like 1 [NPHPL1]) for an NPHP-like nephropathy. In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene. In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells. However, in vivo analyses also revealed a likely cilia-related function; suppression of zebrafish xpnpep3 phenocopied the developmental phenotypes of ciliopathy morphants, and this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal. Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish. Our data highlight an emerging link between mitochondria and ciliary dysfunction, and suggest that further understanding the enzymatic activity and substrates of XPNPEP3 will illuminate novel cystogenic pathways.

Inv acts as a molecular anchor for Nphp3 and Nek8 in the proximal segment of primary cilia

A primary cilium is an antenna-like structure extending from the surface of most vertebrate cells. It is structurally divided along its vertical axis into sub-compartments that include the ciliary tip, the shaft, the ciliary necklace segment, the transitional zone and the basal body. We recently discovered that the shaft of the primary cilia has a distinct molecular compartment, termed the "Inv compartment", which is characterized by the accumulation of Inv at the base of primary cilia. Inv was discovered as a causative gene in inv mutant mice. It was later found to be responsible for the infantile type of nephronophthisis (NPHP2). Nephronophthisis (NPHP) is an autosomal recessive kidney disease. Nine causative genes have been identified, with all examined products thought to function in cilia, basal body and/or centrioles. However, their exact intra-ciliary localization and relationship have not been clear. Here, we report that products of Nphp3 and Nek8 (the mouse orthologs of the causative genes for NPHP3 and NPHP9, respectively) localize to the Inv compartment. We also show that Inv is essential for the compartmental localization of Nphp3 and Nek8, whereas localization of Inv does not require Nphp3 or Nek8. Nphp1 and Nphp4 also localize at the proximal region of the cilium, but not in Inv compartment. Our results indicate that Inv acts as an anchor for Nphp3 and Nek8 in the Inv compartment, and suggest that Inv compartment is a candidate site for intra-ciliary interaction of Inv, Nphp3 and Nek8.

Kusma yakınması ile başvuran 12 aylık kız hasta Ayın Olgusu

Cystic diseases of liver are recognized in infancy and childhood initially Cystic diseases of liver and biliary tract are choledocal cysts autosomal recessive and autosomal dominant polycystic kidney disease congenital hepatic fibrosis and Caroli disease cystic dilatation of intrahepatic bile ducts Choledochal cysts and Caroli disease do not allow biliary flow cause chronic or obstructive cholestasis and progressive liver disease In congenital hepatic fibrosis and polycystic kidney disease there is cystic formations at terminal interlobular bile ducts but cholestasis is not seen They don’t cause liver and biliary tract functional disturbances Turk Arch Ped 2008; 43: 40 5 Key words: Biliary tract cystic diseases liver renal

NEK8 Mutations Affect Ciliary and Centrosomal Localization and May Cause Nephronophthisis

Nephronophthisis, an autosomal recessive kidney disease, is the most frequent genetic cause of chronic renal failure in the first 3 decades of life. Causative mutations in 8 genes (NPHP1-8) have been identified, and homologous mouse models for NPHP2/INVS and NPHP3 have been described. The jck mouse is another model of recessive cystic kidney disease, and this mouse harbors a missense mutation, G448V, in the highly conserved RCC1 domain of Nek8. We hypothesized that mutations in NEK8 might cause nephronophthisis in humans, so we performed mutational analysis in a worldwide cohort of 588 patients. We identified 3 different amino acid changes that were conserved through evolution (L330F, H425Y, and A497P) and that were absent from at least 80 ethnically matched controls. All 3 mutations were within RCC1 domains, and the mutation H425Y was positioned within the same RCC1 repeat as the mouse jck mutation. To test the functional significance of these mutations, we introduced them into full-length mouse Nek8 GFP-tagged cDNA constructs. We transiently overexpressed the constructs in inner medullary collecting duct cells (IMCD-3 cell line) and compared the subcellular localization of mutant Nek8 to wild-type Nek8. All mutant forms of Nek8 showed defects in ciliary localization to varying degrees; the H431Y mutant (human H425Y) was completely absent from cilia and the amount localized to centrosomes was decreased. Overexpression of these mutants did not affect overall ciliogenesis, mitosis, or centriole number. Our genetic and functional data support the assumption that mutations in NEK8 cause nephronophthisis (NPHP9), adding another link between proteins mutated in cystic kidney disease and their localization to cilia and centrosomes.

Mutation analysis in nephronophthisis using a combined approach of homozygosity mapping, CEL I endonuclease cleavage, and direct sequencing

Nephronophthisis (NPHP), an autosomal recessive kidney disease, is the most frequent genetic cause of chronic renal failure in the first three decades of life. Mutations in eight genes (NPHP1-8) have been identified. We here describe a combined approach for mutation screening of NPHP1, NPHP2, NPHP3, NPHP4, and NPHP5 in a worldwide cohort of 470 unrelated patients with NPHP. First, homozygous NPHP1 deletions were detected in 97 patients (21%) by multiplex PCR. Second, 25 patients with infantile NPHP were screened for mutations in inversin (NPHP2/INVS). We detected a novel compound heterozygous frameshift mutation (p.[Q485fs]+[R687fs]), and a homozygous nonsense mutation (p.R899X). Third, 37 patients presenting with NPHP and retinitis pigmentosa (Senior-Løken syndrome [SLS]) were screened for NPHP5/IQCB1 mutations by direct sequencing. We discovered five different (three novel) homozygous premature termination codon (PTC) mutations (p.F142fsX; p.R461X; p.R489X; p.W444X; and c.488-1G>A). The remaining 366 patients were further investigated for mutations in NPHP1, NPHP3, and NPHP4. We applied a "homozygosity only" strategy and typed three highly polymorphic microsatellite markers at the respective loci. A total of 32, eight, and 14 patients showed homozygosity, and were screened by heteroduplex crude celery extract (CEL I) endonuclease digests. The sensitivity of CEL I was established as 92%, as it detected 73 out of 79 different known mutations simply on agarose gels. A total of 10 novel PTC mutations were found in NPHP1 (p.P186fs, p.R347X, p.V492fs, p.Y509X, and c.1884+1G>A), in NPHP3 (c.3812+2T>C and p.R1259X), and in NPHP4 (p.R59X, p.T1004fs, and p.V1091fs). The combined homozygosity mapping and CEL I endonuclease mutation analysis approach allowed us to identify rare mutations in a large cohort of patients at low cost.

Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis

Nephronophthisis (NPHP), an autosomal recessive kidney disease, is the most frequent genetic cause of end-stage renal failure in the first three decades of life. Positional cloning of the six known NPHP genes has linked its pathogenesis to primary cilia function. Here we identify mutation of GLIS2 as causing an NPHP-like phenotype in humans and mice, using positional cloning and mouse transgenics, respectively. Kidneys of Glis2 mutant mice show severe renal atrophy and fibrosis starting at 8 weeks of age. Differential gene expression studies on Glis2 mutant kidneys demonstrate that genes promoting epithelial-to-mesenchymal transition and fibrosis are upregulated in the absence of Glis2. Thus, we identify Glis2 as a transcription factor mutated in NPHP and demonstrate its essential role for the maintenance of renal tissue architecture through prevention of apoptosis and fibrosis.