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1.  Clinico-pathological correlations of congenital and infantile nephrotic syndrome over twenty years 
Pediatric Nephrology (Berlin, Germany)  2014;29(11):2173-2180.
Background
Nephrotic syndrome (NS) presenting early in life is caused by heterogeneous glomerular diseases. We retrospectively evaluated whether histological diagnosis in children presenting with NS in the first year of life predicts remission or progression to end-stage kidney disease (ESKD).
Methods
This is a single centre retrospective review of all children diagnosed with NS before one year of age between 1990 and 2009. All subjects had a renal biopsy, which was independently blindly reviewed by a single renal pathologist for the purpose of this study.
Results
Forty-nine children (25 female) who presented at 0.1–11.6 (median 1.6) months were included with 31 presenting within the first three months of life. Histopathological review diagnostic categories were; 13 Mesangial proliferative glomerulopathy (MesGN), 12 Focal and segmental glomerulosclerosis (FSGS), 11 Finnish type changes, eight Diffuse Mesangial Sclerosis (DMS), three Minimal change disease (MCD) and one each of Dense Deposit Disease (DDD) and Membranous nephropathy. Two children died from haemorrhagic complications of the biopsy. Eight children achieved remission (four MesGN, one Finnish type changes, one FSGS, one MCD and one membranous) with patient and renal survival of 73 % and 43 %, respectively, at follow-up duration of 5–222 (median 73) months (with five lost to follow-up). All children with Finnish-type histopathological changes presented within five months of age. Due to the historical nature of the cohort, genetic testing was only available for 14 children, nine of whom had an identifiable genetic basis (seven NPHS1, one PLCE1 and one ITGA3) with none of these nine children achieving remission. All of them had presented within four months of age and required renal replacement therapy, and two died.
Conclusions
Histopathological findings are varied in children presenting with NS early in life. Whilst groups of histological patterns of disease are associated with differing outcomes, accurate prediction of disease course in a specific case is difficult and more widespread genetic testing may improve the understanding of this group of diseases and their optimal management
doi:10.1007/s00467-014-2856-x
PMCID: PMC4176949  PMID: 24902943
Congenital nephrotic syndrome; Infantile nephrotic syndrome; Histopathology; Genetics; Outcome
2.  Short course daily prednisolone therapy during an upper respiratory tract infection in children with relapsing steroid-sensitive nephrotic syndrome (PREDNOS 2): protocol for a randomised controlled trial 
Trials  2014;15:147.
Background
Relapses of childhood steroid-sensitive nephrotic syndrome (SSNS) are treated with a 4- to 8-week course of high-dose oral prednisolone, which may be associated with significant adverse effects. There is a clear association between upper respiratory tract infection (URTI) and relapse development. Previous studies in developing nations have suggested that introducing a 5- to 7-day course of daily prednisolone during an URTI may prevent a relapse developing and the need for a treatment course of high-dose prednisolone. The aim of PREDNOS 2 is to evaluate the effectiveness of a 6-day course of daily prednisolone therapy during an URTI in reducing the development of a subsequent relapse in a developed nation.
Methods/design
The subjects will be 300 children with relapsing SSNS (≥2 relapses in preceding year), who will be randomised to receive either a 6-day course of daily prednisolone or no change to their current therapy (with the use of placebo to double blind) each time they develop an URTI over 12 months. A strict definition for URTI will be used. Subjects will be reviewed at 3, 6, 9 and 12 months to capture data regarding relapse history, ongoing therapy and adverse effect profile, including behavioural problems and quality of life. A formal health economic analysis will also be performed. The primary end point of the study will be the incidence of URTI-related relapse (3 days of Albustix +++) following the first infection during the 12-month follow-up period. DNA and RNA samples will be collected to identify a potential genetic cause for the disease. Subjects will be recruited from over 100 UK centres with the assistance of the Medicines for Children Research Network.
PREDNOS 2 is funded by the National Institute for Health Research Health Technology Assessment Programme (11/129/261).
Discussion
We propose that PREDNOS 2 will be a pivotal study that will inform the future standard of care for children with SSNS. If it is possible to reduce the disease relapse rate effectively and safely, this will reduce the morbidity and cost associated with drug treatment, notwithstanding hospital admission and parental absence from employment.
Trial registration
Current Controlled Trials (ISRCTN10900733).
doi:10.1186/1745-6215-15-147
PMCID: PMC4030532  PMID: 24767719
Steroid sensitive nephrotic syndrome; Relapse; Upper respiratory tract infection; Prednisolone; Adverse effects; Health economic analysis
3.  Mutation Analysis of 18 Nephronophthisis-associated Ciliopathy Disease Genes using a DNA Pooling and Next-Generation Sequencing Strategy 
Journal of medical genetics  2010;48(2):105-116.
Background
Nephronophthisis-associated ciliopathies (NPHP-AC) comprise a group of autosomal recessive cystic kidney diseases that includes nephronophthisis (NPHP), Senior-Loken syndrome (SLS), Joubert syndrome (JBTS), and Meckel-Gruber syndrome (MKS). To date, causative mutations in NPHP-AC have been described for 18 different genes, rendering mutation analysis tedious and expensive. To overcome the broad genetic locus heterogeneity we devised a strategy of DNA pooling with consecutive massively parallel resequencing (MPR).
Methods
In 120 patients with severe NPHP-AC phenotypes we prepared 5 pools of genomic DNA with 24 patients each which were used as templates in order to PCR-amplify all 376 exons of 18 NPHP-AC genes (NPHP1, INVS, NPHP3, NPHP4, IQCB1, CEP290, GLIS2, RPGRIP1L, NEK8, TMEM67, INPP5E, TMEM216, AHI1, ARL13B, CC2D2A, TTC21B, MKS1, and XPNPEP3). PCR products were then subjected to MPR on a Illumina Genome-Analyzer and mutations were subsequently assigned to their respective mutation carrier via CEL I endonuclease-based heteroduplex screening and confirmed by Sanger sequencing.
Results
For proof of principle we used DNA from patients with known mutations and demonstrated the detection of 22 out of 24 different alleles (92% sensitivity). MPR led to the molecular diagnosis in 30/120 patients (25%) and we identified 54 pathogenic mutations (27 novel) in 7 different NPHP-AC genes. Additionally, in 24 patients we only found single heterozygous variants of unknown significance.
Conclusions
The combined approach of DNA pooling followed by MPR strongly facilitates mutation analysis in broadly heterogeneous single-gene disorders. The lack of mutations in 75% of patients in our cohort indicates further extensive heterogeneity in NPHP-AC.
doi:10.1136/jmg.2010.082552
PMCID: PMC3913043  PMID: 21068128
Next-generation sequencing; Ciliopathy; Nephronophthisis
4.  ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3 
Nature genetics  2013;45(8):951-956.
Nephronophthisis (NPH) is an autosomal recessive cystic kidney disease that leads to renal failure in childhood or adolescence. Most NPHP gene products form molecular networks. We have identified ANKS6 as a new NPHP family member that connects NEK8 (NPHP9) to INVERSIN (INVS, NPHP2) and NPHP3 to form a distinct NPHP module. ANKS6 localizes to the proximal cilium and knockdown experiments in zebrafish and Xenopus confirmed a role in renal development. Genetic screening identified six families with ANKS6 mutations and NPH, including severe cardiovascular abnormalities, liver fibrosis and situs inversus. The oxygen sensor HIF1AN (FIH) hydroxylates ANKS6 and INVS, while knockdown of Hif1an in Xenopus resembled the loss of other NPHP proteins. HIF1AN altered the composition of the ANKS6/INVS/NPHP3 module. Network analyses, uncovering additional putative NPHP-associated genes, placed ANKS6 at the center of the NPHP module, explaining the overlapping disease manifestation caused by mutations of either ANKS6, NEK8, INVS or NPHP3.
doi:10.1038/ng.2681
PMCID: PMC3786259  PMID: 23793029
5.  Epilepsy in kcnj10 Morphant Zebrafish Assessed with a Novel Method for Long-Term EEG Recordings 
PLoS ONE  2013;8(11):e79765.
We aimed to develop and validate a reliable method for stable long-term recordings of EEG activity in zebrafish, which is less prone to artifacts than current invasive techniques. EEG activity was recorded with a blunt electrolyte-filled glass pipette placed on the zebrafish head mimicking surface EEG technology in man. In addition, paralysis of agarose-embedded fish using D-tubocurarine excluded movement artifacts associated with epileptic activity. This non-invasive recording technique allowed recordings for up to one hour and produced less artifacts than impaling the zebrafish optic tectum with a patch pipette. Paralyzed fish survived, and normal heartbeat could be monitored for over 1h. Our technique allowed the demonstration of specific epileptic activity in kcnj10a morphant fish (a model for EAST syndrome) closely resembling epileptic activity induced by pentylenetetrazol. This new method documented that seizures in the zebrafish EAST model were ameliorated by pentobarbitone, but not diazepam, validating its usefulness. In conclusion, non-invasive recordings in paralyzed EAST syndrome zebrafish proved stable, reliable and robust, showing qualitatively similar frequency spectra to those obtained from pentylenetetrazol-treated fish. This technique may prove particularly useful in zebrafish epilepsy models that show infrequent or conditional seizure activity.
doi:10.1371/journal.pone.0079765
PMCID: PMC3828195  PMID: 24244558
6.  Nephrocalcinosis (Enamel Renal Syndrome) Caused by Autosomal Recessive FAM20A Mutations 
Jaureguiberry, Graciana | De la Dure-Molla, Muriel | Parry, David | Quentric, Mickael | Himmerkus, Nina | Koike, Toshiyasu | Poulter, James | Klootwijk, Enriko | Robinette, Steven L. | Howie, Alexander J. | Patel, Vaksha | Figueres, Marie-Lucile | Stanescu, Horia C. | Issler, Naomi | Nicholson, Jeremy K. | Bockenhauer, Detlef | Laing, Christopher | Walsh, Stephen B. | McCredie, David A. | Povey, Sue | Asselin, Audrey | Picard, Arnaud | Coulomb, Aurore | Medlar, Alan J. | Bailleul-Forestier, Isabelle | Verloes, Alain | Le Caignec, Cedric | Roussey, Gwenaelle | Guiol, Julien | Isidor, Bertrand | Logan, Clare | Shore, Roger | Johnson, Colin | Inglehearn, Christopher | Al-Bahlani, Suhaila | Schmittbuhl, Matthieu | Clauss, François | Huckert, Mathilde | Laugel, Virginie | Ginglinger, Emmanuelle | Pajarola, Sandra | Spartà, Giuseppina | Bartholdi, Deborah | Rauch, Anita | Addor, Marie-Claude | Yamaguti, Paulo M. | Safatle, Heloisa P. | Acevedo, Ana Carolina | Martelli-Júnior, Hercílio | dos Santos Netos, Pedro E. | Coletta, Ricardo D. | Gruessel, Sandra | Sandmann, Carolin | Ruehmann, Denise | Langman, Craig B. | Scheinman, Steven J. | Ozdemir-Ozenen, Didem | Hart, Thomas C. | Hart, P. Suzanne | Neugebauer, Ute | Schlatter, Eberhard | Houillier, Pascal | Gahl, William A. | Vikkula, Miikka | Bloch-Zupan, Agnès | Bleich, Markus | Kitagawa, Hiroshi | Unwin, Robert J. | Mighell, Alan | Berdal, Ariane | Kleta, Robert
Nephron. Physiology  2013;122(0):1-6.
Background/Aims
Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood.
Methods
We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing.
Results
All patients had biallelic FAM20A mutations segregating with the disease; 20 different mutations were identified.
Conclusions
This autosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis.
doi:10.1159/000349989
PMCID: PMC3782194  PMID: 23434854
Nephrolithiasis; Urolithiasis; Amelogenesis imperfecta; FAM20B; FAM20C
7.  Generation and validation of a zebrafish model of EAST (epilepsy, ataxia, sensorineural deafness and tubulopathy) syndrome 
Disease Models & Mechanisms  2013;6(3):652-660.
SUMMARY
Recessive mutations in KCNJ10, which encodes an inwardly rectifying potassium channel, were recently identified as the cause of EAST syndrome, a severe and disabling multi-organ disorder consisting of epilepsy, ataxia, sensorineural deafness and tubulopathy that becomes clinically apparent with seizures in infancy. A Kcnj10 knockout mouse shows postnatal mortality and is therefore not suitable for drug discovery. Because zebrafish are ideal for in vivo screening for potential therapeutics, we tested whether kcnj10 knockdown in zebrafish would fill this need. We cloned zebrafish kcnj10 and demonstrated that its function is equivalent to that of human KCNJ10. We next injected splice- and translation-blocking kcnj10 antisense morpholino oligonucleotides and reproduced the cardinal symptoms of EAST syndrome – ataxia, epilepsy and renal tubular defects. Several of these phenotypes could be assayed in an automated manner. We could rescue the morphant phenotype with complementary RNA (cRNA) encoding human wild-type KCNJ10, but not with cRNA encoding a KCNJ10 mutation identified in individuals with EAST syndrome. Our results suggest that zebrafish will be a valuable tool to screen for compounds that are potentially therapeutic for EAST syndrome or its individual symptoms. Knockdown of kcnj10 represents the first zebrafish model of a salt-losing tubulopathy, which has relevance for blood pressure control.
doi:10.1242/dmm.009480
PMCID: PMC3634649  PMID: 23471908
8.  Nephrocalcinosis (Enamel Renal Syndrome) Caused by Autosomal Recessive FAM20A Mutations 
Jaureguiberry, Graciana | De la Dure-Molla, Muriel | Parry, David | Quentric, Mickael | Himmerkus, Nina | Koike, Toshiyasu | Poulter, James | Klootwijk, Enriko | Robinette, Steven L. | Howie, Alexander J. | Patel, Vaksha | Figueres, Marie-Lucile | Stanescu, Horia C. | Issler, Naomi | Nicholson, Jeremy K. | Bockenhauer, Detlef | Laing, Christopher | Walsh, Stephen B. | McCredie, David A. | Povey, Sue | Asselin, Audrey | Picard, Arnaud | Coulomb, Aurore | Medlar, Alan J. | Bailleul-Forestier, Isabelle | Verloes, Alain | Le Caignec, Cedric | Roussey, Gwenaelle | Guiol, Julien | Isidor, Bertrand | Logan, Clare | Shore, Roger | Johnson, Colin | Inglehearn, Christopher | Al-Bahlani, Suhaila | Schmittbuhl, Matthieu | Clauss, François | Huckert, Mathilde | Laugel, Virginie | Ginglinger, Emmanuelle | Pajarola, Sandra | Spartà, Giuseppina | Bartholdi, Deborah | Rauch, Anita | Addor, Marie-Claude | Yamaguti, Paulo M. | Safatle, Heloisa P. | Acevedo, Ana Carolina | Martelli-Júnior, Hercílio | dos Santos Netos, Pedro E. | Coletta, Ricardo D. | Gruessel, Sandra | Sandmann, Carolin | Ruehmann, Denise | Langman, Craig B. | Scheinman, Steven J. | Ozdemir-Ozenen, Didem | Hart, Thomas C. | Hart, P. Suzanne | Neugebauer, Ute | Schlatter, Eberhard | Houillier, Pascal | Gahl, William A. | Vikkula, Miikka | Bloch-Zupan, Agnès | Bleich, Markus | Kitagawa, Hiroshi | Unwin, Robert J. | Mighell, Alan | Berdal, Ariane | Kleta, Robert
Nephron. Physiology  2013;122(1-2):1-6.
Background/Aims
Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood.
Methods
We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing.
Results
All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified.
Conclusions
This au-tosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis.
doi:10.1159/000349989
PMCID: PMC3782194  PMID: 23434854
Nephrolithiasis; Urolithiasis; Amelogenesis imperfecta; FAM20B; FAM20C

9.  Integrin α3 Mutations with Kidney, Lung, and Skin Disease 
The New England Journal of Medicine  2012;366(16):1508-1514.
SUMMARY
Integrin α3 is a transmembrane integrin receptor subunit that mediates signals between the cells and their microenvironment. We identified three patients with homozygous mutations in the integrin α3 gene that were associated with disrupted basement-membrane structures and compromised barrier functions in kidney, lung, and skin. The patients had a multiorgan disorder that included congenital nephrotic syndrome, interstitial lung disease, and epidermolysis bullosa. The renal and respiratory features predominated, and the lung involvement accounted for the lethal course of the disease. Although skin fragility was mild, it provided clues to the diagnosis.
doi:10.1056/NEJMoa1110813
PMCID: PMC3341404  PMID: 22512483
10.  Mutations in Kelch-like 3 and Cullin 3 cause hypertension and electrolyte abnormalities 
Nature  2012;482(7383):98-102.
Hypertension affects one billion people and is a principal reversible risk factor for cardiovascular disease. A rare Mendelian syndrome, pseudohypoaldosteronism type II (PHAII), featuring hypertension, hyperkalemia, and metabolic acidosis, has revealed previously unrecognized physiology orchestrating the balance between renal salt reabsorption versus K+ and H+ excretion1. We used exome sequencing to identify mutations in Kelch-like 3 (KLHL3) or Cullin 3 (CUL3) in 41 PHAII kindreds. KLHL3 mutations are either recessive or dominant, while CUL3 mutations are dominant and predominantly de novo. CUL3 and BTB-Kelch proteins such as KLHL3 are components of Cullin/RING E3 ligase complexes (CRLs) that ubiquitinate substrates bound to Kelch propeller domains2–8. Dominant KLHL3 mutations are clustered in short segments within the Kelch propeller and BTB domains implicated in substrate9 and Cullin5 binding, respectively. Diverse CUL3 mutations all result in skipping of exon 9, producing an in-frame deletion. Because dominant KLHL3 and CUL3 mutations both phenocopy recessive loss-of-function KLHL3 mutations, they may abrogate ubiquitination of KLHL3 substrates. Disease features are reversed by thiazide diuretics, which inhibit the Na-Cl cotransporter (NCC) in the distal nephron of the kidney; KLHL3 and CUL3 are expressed in this location, suggesting a mechanistic link between KLHL3/CUL3 mutations, increased Na-Cl reabsorption, and disease pathogenesis. These findings demonstrate the utility of exome sequencing in disease gene identification despite combined complexities of locus heterogeneity, mixed models of transmission, and frequent de novo mutation, and establish a fundamental role for KLHL3/CUL3 in blood pressure, K+, and pH homeostasis.
doi:10.1038/nature10814
PMCID: PMC3278668  PMID: 22266938
11.  Epilepsy, Ataxia, Sensorineural Deafness, Tubulopathy, and KCNJ10 Mutations 
The New England Journal of Medicine  2009;360(19):1960-1970.
BACKGROUND
Five children from two consanguineous families presented with epilepsy beginning in infancy and severe ataxia, moderate sensorineural deafness, and a renal salt-losing tubulopathy with normotensive hypokalemic metabolic alkalosis. We investigated the genetic basis of this autosomal recessive disease, which we call the EAST syndrome (the presence of epilepsy, ataxia, sensorineural deafness, and tubulopathy).
METHODS
Whole-genome linkage analysis was performed in the four affected children in one of the families. Newly identified mutations in a potassium-channel gene were evaluated with the use of a heterologous expression system. Protein expression and function were further investigated in genetically modified mice.
RESULTS
Linkage analysis identified a single significant locus on chromosome 1q23.2 with a lod score of 4.98. This region contained the KCNJ10 gene, which encodes a potassium channel expressed in the brain, inner ear, and kidney. Sequencing of this candidate gene revealed homozygous missense mutations in affected persons in both families. These mutations, when expressed heterologously in xenopus oocytes, caused significant and specific decreases in potassium currents. Mice with Kcnj10 deletions became dehydrated, with definitive evidence of renal salt wasting.
CONCLUSIONS
Mutations in KCNJ10 cause a specific disorder, consisting of epilepsy, ataxia, sensorineural deafness, and tubulopathy. Our findings indicate that KCNJ10 plays a major role in renal salt handling and, hence, possibly also in blood-pressure maintenance and its regulation.
doi:10.1056/NEJMoa0810276
PMCID: PMC3398803  PMID: 19420365
12.  Nineteen novel NPHS1 mutations in a worldwide cohort of patients with congenital nephrotic syndrome (CNS) 
Nephrology Dialysis Transplantation  2010;25(9):2970-2976.
Background. Recessive mutations in the NPHS1 gene encoding nephrin account for ∼40% of infants with congenital nephrotic syndrome (CNS). CNS is defined as steroid-resistant nephrotic syndrome (SRNS) within the first 90 days of life. Currently, more than 119 different mutations of NPHS1 have been published affecting most exons.
Methods. We here performed mutational analysis of NPHS1 in a worldwide cohort of 67 children from 62 different families with CNS.
Results. We found bi-allelic mutations in 36 of the 62 families (58%) confirming in a worldwide cohort that about one-half of CNS is caused by NPHS1 mutations. In 26 families, mutations were homozygous, and in 10, they were compound heterozygous. In an additional nine patients from eight families, only one heterozygous mutation was detected. We detected 37 different mutations. Nineteen of the 37 were novel mutations (∼51.4%), including 11 missense mutations, 4 splice-site mutations, 3 nonsense mutations and 1 small deletion. In an additional patient with later manifestation, we discovered two further novel mutations, including the first one affecting a glycosylation site of nephrin.
Conclusions. Our data hereby expand the spectrum of known mutations by 17.6%. Surprisingly, out of the two siblings with the homozygous novel mutation L587R in NPHS1, only one developed nephrotic syndrome before the age of 90 days, while the other one did not manifest until the age of 2 years. Both siblings also unexpectedly experienced an episode of partial remission upon steroid treatment.
doi:10.1093/ndt/gfq088
PMCID: PMC2948833  PMID: 20172850
mutation analysis; nephrotic syndrome; NPHS1
13.  Uncovering Genomic Causes of Co-Morbidity in Epilepsy: Gene-Driven Phenotypic Characterization of Rare Microdeletions 
PLoS ONE  2011;6(8):e23182.
Background
Patients with epilepsy often suffer from other important conditions. The existence of such co-morbidities is frequently not recognized and their relationship with epilepsy usually remains unexplained.
Methodology/Principal Findings
We describe three patients with common, sporadic, non-syndromic epilepsies in whom large genomic microdeletions were found during a study of genetic susceptibility to epilepsy. We performed detailed gene-driven clinical investigations in each patient. Disruption of the function of genes in the deleted regions can explain co-morbidities in these patients.
Conclusions/Significance
Co-morbidities in patients with epilepsy can be part of a genomic abnormality even in the absence of (known) congenital malformations or intellectual disabilities. Gene-driven phenotype examination can also reveal clinically significant unsuspected condition.
doi:10.1371/journal.pone.0023182
PMCID: PMC3157359  PMID: 21858020
14.  Mutations in the Human Laminin β2 (LAMB2) Gene and the Associated Phenotypic Spectrum 
Human mutation  2010;31(9):992-1002.
Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin β2 which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families. The majority of disease-causing LAMB2 mutations are truncating, consistent with the hypothesis that loss of laminin β2 function is the molecular basis of Pierson syndrome. While truncating mutations are distributed across the entire gene, missense mutations are clearly clustered in the N-terminal LN domain, which is important for intermolecular interactions. There is an association of missense mutations and small in frame deletions with a higher mean age at onset of renal disease and with absence of neurologic abnormalities, thus suggesting that at least some of these may represent hypomorphic alleles. Nevertheless, genotype alone does not appear to explain the full range of clinical variability, and therefore hitherto unidentified modifiers are likely to exist.
doi:10.1002/humu.21304
PMCID: PMC2978072  PMID: 20556798
LAMB2; Pierson syndrome; nephrotic syndrome; autosomal recessive; podocyte; laminin; ocular malformation
15.  Renal malformations associated with mutations of developmental genes: messages from the clinic 
Pediatric Nephrology (Berlin, Germany)  2010;25(11):2247-2255.
Renal tract malformations (RTMs) account for about 40% of children with end-stage renal failure. RTMs can be caused by mutations of genes normally active in the developing kidney and lower renal tract. Moreover, some RTMs occur in the context of multi-organ malformation syndromes. For these reasons, and because genetic testing is becoming more widely available, pediatric nephrologists should work closely with clinical geneticists to make genetic diagnoses in children with RTMs, followed by appropriate family counseling. Here we highlight families with renal cysts and diabetes, renal coloboma and Fraser syndromes, and a child with microdeletion of chromosome 19q who had a rare combination of malformations. Such diagnoses provide families with often long-sought answers to the question “why was our child born with kidney disease”. Precise genetic diagnoses will also help to define cohorts of children with RTMs for long-term clinical outcome studies.
doi:10.1007/s00467-010-1578-y
PMCID: PMC2937138  PMID: 20603712
Deletion; Gene; Mutation; Malformation; Renal tract
16.  Neurological features of epilepsy, ataxia, sensorineural deafness, tubulopathy syndrome 
AIM
Recently, we reported a previously unrecognized symptom constellation comprising epilepsy, ataxia, sensorineural deafness, and tubulopathy (EAST syndrome) associated with recessive mutations in the KCNJ10 gene. Here, we provide a detailed characterization of the clinical features of the syndrome to aid patient management with respect to diagnosis, prognostic counselling, and identification of best treatment modalities.
METHOD
We conducted a retrospective review of the detailed neurological and neuroradiological features of nine children (four females, five males; age range at last examination 6–20y) with genetically proven EAST syndrome.
RESULTS
All children presented with tonic–clonic seizures in infancy. Later, non-progressive, cerebellar ataxia and hearing loss were noted. Whilst seizures mostly responded well to treatment, ataxia proved to be the most debilitating feature, with three patients non-ambulant. All available magnetic resonance imaging (MRI) revealed subtle symmetrical signal changes in the cerebellar dentate nuclei. Moreover, four patients had a small corpus callosum and brainstem hypoplasia, and three had a small spinal cord. Regional quantitative volumetric analysis of the images confirmed the corpus callosum and brainstem hypoplasia and showed further patterns of variation from the norm.
INTERPRETATION
The neurological features of EAST syndrome appear to be non-progressive, which is important for prognostic counselling. The spectrum of EAST syndrome includes consistent abnormalities on brain MRI, which may aid diagnosis. Further longitudinal documentation is required to determine the true natural history of the disorder.
doi:10.1111/dmcn.12171
PMCID: PMC4298033  PMID: 23924083

Results 1-16 (16)