Background and objectives: Hepatocyte nuclear factor 1␤ (HNF1␤) is a transcription factor that is critical for the development of kidney and pancreas. In humans, mutations in HNF1B lead to congenital anomalies of the kidney and urinary tract, pancreas atrophy, and maturity-onset diabetes of the young type 5 and genital malformations.Design, setting, participants, & measurements: We report HNF1B screening in a cohort of 377 unrelated cases with various kidney phenotypes (hyperechogenic kidneys with size not more than ؉3 SD, multicystic kidney disease, renal agenesis, renal hypoplasia, cystic dysplasia, or hyperuricemic tubulointerstitial nephropathy not associated with UMOD mutation).Results: We found a heterozygous mutation in 75 (19.9%) index cases, consisting of a deletion of the whole gene in 42, deletion of one exon in one, and small mutations in 32. Eighteen mutations were novel. De novo mutations accounted for 66% of deletions and 40% of small mutations. In patients who carried HNF1B mutation and for whom we were able to study prenatal ultrasonography (56 probands), isolated hyperechogenic kidneys with normal or slightly enhanced size were the more frequent (34 of 56) phenotype before birth. Various other prenatal renal phenotypes were associated with HNF1B mutations, at a lesser frequency. Diabetes developed in four probands. Hyperuricemia and hypomagnesemia, although not systematically investigated, were frequently associated.Conclusions: This large series showed that the severity of the renal disease associated with HNF1B mutations was extremely variable (from prenatal renal failure to normal renal function in adulthood) and was not correlated with the genotype.

SummaryBackground UMOD mutations cause familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic kidney disease (MCKD), although these phenotypes are nonspecific.Design, setting, participants, & measurements We reviewed cases of UMOD mutations diagnosed in the genetic laboratories of Necker Hospital (Paris, France) and of Université Catholique de Louvain (Brussels, Belgium). We also analyzed patients with MCKD/FJHN but no UMOD mutation. To determine thresholds for hyperuricemia and uric-acid excretion fraction (UAEF) according to GFR, these parameters were analyzed in 1097 patients with various renal diseases and renal function levels.Results Thirty-seven distinct UMOD mutations were found in 109 patients from 45 families, all in exon 4 or 5 except for three novel mutations in exon 8. Median renal survival was 54 years. The type of mutation had a modest effect on renal survival, and intrafamilial variability was high. Detailed data available in 70 patients showed renal cysts in 24 (34.3%) of nonspecific localization in most patients. Uricemia was Ͼ75th percentile in 31 (71.4%) of 42 patients not under dialysis or allopurinol therapy. UAEF (n ϭ 27) was Ͻ75th percentile in 70.4%. Among 136 probands with MCKD/FJHN phenotype, UMOD mutation was found in 24 (17.8%). Phenotype was not accurately predictive of UMOD mutation. Six probands had HNF1B mutations.Conclusions Hyperuricemia disproportionate to renal function represents the hallmark of renal disease caused by UMOD mutation. Renal survival is highly variable in patients with UMOD mutation. Our data also add novel insights into the interpretation of uricemia and UAEF in patients with chronic kidney diseases.

Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS in the maintenance of blood pressure and renal blood flow during the life of a human fetus. Renal hypoperfusion, whether genetic or secondary to a variety of diseases, precludes the normal development/ differentiation of proximal tubules. The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis.

Mutations in NPHS1, which encodes nephrin, are the main causes of congenital nephrotic syndrome (CNS) in Finnish patients, whereas mutations in NPHS2, which encodes podocin, are typically responsible for childhood-onset steroid-resistant nephrotic syndrome in European populations. Genotype-phenotype correlations are not well understood in non-Finnish patients. We evaluated the clinical presentation, kidney histology, and disease progression in non-Finnish CNS cases by mutational screening in 107 families (117 cases) by sequencing the entire coding regions of NPHS1, NPHS2, PLCE1, WT1, LAMB2, PDSS2, COQ2, and NEPH1. We found that CNS describes a heterogeneous group of disorders in non-Finnish populations. We identified nephrin and podocin mutations in most families and only rarely found mutations in genes implicated in other hereditary forms of NS. In approximately 20% of cases, we could not identify the underlying genetic cause. Consistent with the major role of nephrin at the slit diaphragm, NPHS1 mutations associated with an earlier onset of disease and worse renal outcomes than NPHS2 mutations. Milder cases resulting from mutant NPHS1 had either two mutations in the cytoplasmic tail or two missense mutations in the extracellular domain, including at least one that preserved structure and function. In addition, we extend the spectrum of known NPHS1 mutations by describing long NPHS1 deletions. In summary, these data demonstrate that CNS is not a distinct clinical entity in non-Finnish populations but rather a clinically and genetically heterogeneous group of disorders.

Through linkage analysis and candidate gene sequencing, we identified three unrelated families with the autosomal-dominant inheritance of early onset anemia, hypouricosuric hyperuricemia, progressive kidney failure, and mutations resulting either in the deletion (p.Leu16del) or the amino acid exchange (p.Leu16Arg) of a single leucine residue in the signal sequence of renin. Both mutations decrease signal sequence hydrophobicity and are predicted by bioinformatic analyses to damage targeting and cotranslational translocation of preprorenin into the endoplasmic reticulum (ER). Transfection and in vitro studies confirmed that both mutations affect ER translocation and processing of nascent preprorenin, resulting either in reduced (p.Leu16del) or abolished (p.Leu16Arg) prorenin and renin biosynthesis and secretion. Expression of renin and other components of the renin-angiotensin system was decreased accordingly in kidney biopsy specimens from affected individuals. Cells stably expressing the p.Leu16del protein showed activated ER stress, unfolded protein response, and reduced growth rate. It is likely that expression of the mutant proteins has a dominant toxic effect gradually reducing the viability of renin-expressing cells. This alters the intrarenal renin-angiotensin system and the juxtaglomerular apparatus functionality and leads to nephron dropout and progressive kidney failure. Our findings provide insight into the functionality of renin-angiotensin system and stress the importance of renin analysis in families and individuals with early onset hyperuricemia, anemia, and progressive kidney failure.

Nephronophthisis is an autosomal recessive chronic tubulointerstitial disease that progresses to end-stage renal disease (ESRD) in about 10% of cases during infancy. Mutations in the INVS (NPHP2) gene were found in a few patients with infantile nephronophthisis. Mutations of NPHP3, known to be associated with adolescent nephronophthisis, were found in two patients with early-onset ESRD. Here we screened 43 families with infantile nephronophthisis (ESRD less than 5 years of age) for NPHP2 and NPHP3 mutations and determined genotype-phenotype correlations. In this cohort there were 16 families with NPHP2 mutations and NPHP3 mutations in seven. Three patients carried only one heterozygous mutation in NPHP3. ESRD arose during the first 2 years of life in 16 of 18 patients with mutations in NPHP2, but in only two patients with mutations in NPHP3. Renal morphology, characterized by hyper-echogenic kidneys on ultrasound and tubular lesions with interstitial fibrosis on histology, was similar in the two patient groups. The kidney sizes were highly diverse and ultrasound-visualized cysts were present in a minority of cases. Extra-renal anomalies were found in 80% of the entire cohort including hepatic involvement (50%), cardiac valve or septal defects (20%) and recurrent bronchial infections (18%). We show that NPHP3 mutations in both infantile and adolescent nephronophthisis point to a common pathophysiological mechanism despite their different clinical presentations.

Background: Mutations in the PLCE1 gene encoding phospholipase C epsilon 1 (PLCε1)

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