PubMed Health⌕ Search

Biomedical subjects

Lisa Guay-Woodford

Publications and source records attributed to Lisa Guay-Woodford.

11 recordsLinked to original sources
PubMed2025

Polygenic Risk Scores and HLA Class II Variants are Biomarkers of Corticosteroid Response in Childhood Nephrotic Syndrome.

INTRODUCTION: Nephrotic syndrome (NS), a common glomerular disease in children, is classified based on response to corticosteroid therapy as either steroid-sensitive nephrotic syndrome (SSNS), or steroid-resistant nephrotic syndrome (SRNS). However, there are currently no reliable predictors of therapy response at initial clinical presentation. METHODS: We conducted genome-wide association studies, developed polygenic risk scores (PRS) for therapy response and analyzed classical HLA alleles in 1,997 (994 discovery and 1,003 replication/validation cohorts) previously unstudied children with NS and 3,558 ancestry-matched controls. RESULTS: A significant association with HLA loci defined by variants in HLA-DQB1, HLA-DRB1, and HLA-DQA1 were found for SSNS (but not SRNS), along with a second immune-related SSNS locus: CLEC16A. A PRS that discriminates between SSNS and SRNS was validated in two independent cohorts. The HLA haplotype HLA- DRB1*07:01~DQA1*02:01~DQB1*02:02 was associated with ~4 times the risk of developing SSNS. A model incorporating HLA haplotype, PRS score, and age at onset of the disease was the best predictor of steroid responsiveness with an AUC of 0.68-0.70 and an overall classification accuracy of SSNS versus SRNS of 67-71%. CONCLUSIONS: Our findings confirm that SSNS (unlike SRNS) is an immune-mediated HLA-associated disorder. The PRS for therapy response and HLA haplotype can serve as biomarkers and provide a foundation for more accurate diagnoses and tailored and individualized treatment.

HLA haplotype↗
PubMed2006

Predominant extrahepatic biliary disease in autosomal recessive polycystic kidney disease: a new association.

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 approximately 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.

Adolescent↗
PubMed2006

Galectin-3 associates with the primary cilium and modulates cyst growth in congenital polycystic kidney disease.

Several lines of evidence implicate the beta-galactoside-binding lectin galectin-3 in development and pathological processes in renal collecting ducts: galectin-3 is expressed in the ureteric bud/collecting duct lineage during nephrogenesis, modulates collecting duct growth/differentiation in vitro, and is expressed in human autosomal recessive polycystic kidney disease in cyst epithelia, almost all of which arise from collecting ducts. Moreover, exogenous galectin-3 restricts growth of cysts generated by Madin-Darby canine kidney collecting duct-derived cells in three-dimensional culture in collagen. Using the cpk mouse model of recessively inherited polycystic kidney disease, we observed widespread galectin-3 mRNA and protein in cyst epithelia. Exogenous galectin-3 reduced cyst formation in suspension culture, and mice-null mutant for galectin-3 had more extensive renal cysts in vivo. Galectin-3 was also detected for the first time in the centrosome/primary cilium, which has been implicated in diverse polycystic kidney disease. Cilia structure/number appeared normal in galectin-3-null mutants. Finally, paclitaxel, a therapy that retards polycystic kidney disease in cpk mice, increased extracellular galectin-3, in which the lectin could potentially interact with cilia. These data raise the possibility that galectin-3 may act as a natural brake on cystogenesis in cpk mice, perhaps via ciliary roles.

Animals↗
PubMed2004

PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD).

Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of childhood renal- and liver-related morbidity and mortality. The clinical spectrum is widely variable. About 30 to 50% of affected individuals die in the neonatal period, while others survive into adulthood. ARPKD is caused by mutations in the PKHD1 (polycystic kidney and hepatic disease 1) gene on chromosome 6p12, which is among the largest human genes, with a minimum of 86 exons assembled into a variety of alternatively spliced transcripts. The longest continuous open reading frame is predicted to yield a 4,074-aa (447-kDa) multidomain integral membrane protein (fibrocystin/polyductin) of unknown function. This update compiles all known PKHD1 mutations and polymorphisms/sequence variants. Mutations were found to be scattered throughout the gene without evidence of clustering at specific sites. Most PKHD1 mutations are unique to single families ("private mutations") hampering genotype-phenotype correlations. Correlations have been drawn for the type of mutation rather than for the site of individual mutations. All patients carrying two truncating mutations displayed a severe phenotype with perinatal or neonatal demise, while patients surviving the neonatal period bear at least one missense mutation. However, some missense changes are obviously as devastating as truncating mutations. The present article intends 1) to provide an overview of PKHD1 mutations and polymorphisms/sequence variants identified so far, 2) to discuss potential genotype-phenotype correlations, and 3) to review them in the context of their clinical implications. A constantly updated list of mutations is available online (www.humgen.rwth-aachen.de) and investigators are invited to submit their novel data to this PKHD1 mutation database.

DNA Mutational Analysis↗
PubMed2003

Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1).

Autosomal recessive polycystic kidney disease (ARPKD/PKHD1) is an important cause of renal-related and liver-related morbidity and mortality in childhood. Recently mutations in the PKHD1 gene on chromosome 6p21.1-p12 have been identified as the molecular cause of ARPKD. The longest continuous open reading frame (ORF) is encoded by a 67-exon transcript and predicted to yield a 4074-amino acid protein ("polyductin") of thus far unknown function. By now, a total of 29 different PKHD1 mutations have been described. This study reports mutation screening in 90 ARPKD patients and identifies mutations in 110 alleles making up a detection rate of 61%. Thirty-four of the detected mutations have not been reported previously. Two underlying mutations in 40 patients and one mutation in 30 cases are disclosed, and no mutation was detected on the remaining chromosomes. Mutations were found to be scattered throughout the gene without evidence of clustering at specific sites. About 45% of the changes were predicted to truncate the protein. All missense mutations were nonconservative, with the affected amino acid residues found to be conserved in the murine polyductin orthologue. One recurrent missense mutation (T36M) likely represents a mutational hotspot and occurs in a variety of populations. Two founder mutations (R496X and V3471G) make up about 60% of PKHD1 mutations in the Finnish population. Preliminary genotype-phenotype correlations could be established for the type of mutation rather than for the site of the individual mutation. All patients carrying two truncating mutations displayed a severe phenotype with perinatal or neonatal demise. PKHD1 mutation analysis is a powerful tool to establish the molecular cause of ARPKD in a given family. Direct identification of mutations allows an unequivocal diagnosis and accurate genetic counseling even in families displaying diagnostic challenges.

Adolescent↗
PubMed2002

Confirmation of the ATP6B1 gene as responsible for distal renal tubular acidosis.

Primary distal renal tubular acidosis (dRTA) type I is a hereditary renal tubular disorder, which is characterized by impaired renal acid secretion resulting in metabolic acidosis. Clinical symptoms are nephrocalcinosis, nephrolithiasis, osteomalacia, and growth retardation. Biochemical alterations consist of hyperchloremic metabolic acidosis, hypokalemia with muscle weakness, hypercalciuria, and inappropriately raised urinary pH. Autosomal dominant and rare forms of recessive dRTA are known to be caused by mutations in the gene for the anion exchanger AE1. In order to identify a gene responsible for recessive dRTA, we performed a total genome scan with 303 polymorphic microsatellite markers in six consanguineous families with recessive dRTA from Turkey. In four of these there was an association with sensorineural deafness. The total genome scan yielded regions of homozygosity by descent in all six families on chromosomes 1, 2, and 10 as positional candidate region. In one of these regions the gene ATP6B1for the ss1 subunit of the vacuolar H(+)-ATPase is localized, which has recently been identified as causative for recessive dRTA with sensorineural deafness. Therefore, we conducted mutational analysis in 15 families and identified potential loss-of-function mutations in ATP6B1in 8. We thus confirmed that defects in this gene are responsible for recessive dRTA with sensorineural deafness.

Acidosis, Renal Tubular↗
PubMed2002

Identification and characterization of Pkhd1, the mouse orthologue of the human ARPKD gene.

PKHD1, the gene mutated in human autosomal recessive polycystic kidney disease has recently been identified. Its translation products are predicted to belong to a superfamily of proteins involved in the regulation of cellular adhesion and repulsion. One notable aspect of the gene is its unusually complex pattern of splicing. This study shows that mouse Pkhd1 and its translation products have very similar properties to its human orthologue. Mouse Pkhd1 extends over approximately 500 kb of genomic DNA, includes a minimum of 68 nonoverlapping exons, and exhibits a complex pattern of splicing. The longest ORF encodes a protein of 4059aa predicted to have an N-terminal signal peptide, multiple IPTs and PbH1 repeats, a single transmembrane span (TM), and a short cytoplasmic C-terminus. Although the protein sequence is generally well conserved (approximately 73% average identity), the C-termini share only 55% identity. The pattern of Pkhd1 expression by in situ hybridization was also examined in developing and adult mouse tissues over a range of ages (E12.5 to 3 mo postnatal). High levels of expression were present in renal and biliary tubular structures at all time points examined. Prominent Pkhd1 signals were also found in a number of other organs and tissues. Tissue-specific differences in transcript expression were revealed through the use of single exon probes. These data show that key features of human PKHD1 are highly conserved in the mouse and suggest that the complicated pattern of splicing is likely to be functionally important.

Animals↗
PubMed2000

Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome.

ABSTRACT.: Inherited hypokalemic renal tubulopathies are differentiated into at least three clinical subtypes: (1) the Gitelman variant of Bartter syndrome (GS); (2) hyperprostaglandin E syndrome, the antenatal variant of Bartter syndrome (HPS/aBS); and (3) the classic Bartter syndrome (cBS). Hypokalemic metabolic alkalosis and renal salt wasting are the common characteristics of all three subtypes. Hypocalciuria and hypomagnesemia are specific clinical features of Gitelman syndrome, while HPS/aBS is a life-threatening disorder of the newborn with polyhydramnios, premature delivery, hyposthenuria, and nephrocalcinosis. The Gitelman variant is uniformly caused by mutations in the gene for the thiazide-sensitive NaCl-cotransporter NCCT (SLC12A3) of the distal tubule, while HPS/aBS is caused by mutations in the gene for either the furosemide-sensitive NaK-2Cl-cotransporter NKCC2 (SLC12A1) or the inwardly rectifying potassium channel ROMK (KCNJ1). Recently, mutations in a basolateral chloride channel CLC-Kb (CLCNKB) have been described in a subset of patients with a Bartter-like phenotype typically lacking nephrocalcinosis. In this study, the screening for CLCNKB mutations showed 20 different mutations in the affected children from 30 families. The clinical characterization revealed a highly variable phenotype ranging from episodes of severe volume depletion and hypokalemia during the neonatal period to almost asymptomatic patients diagnosed during adolescence. This study adds 16 novel mutations to the nine already described, providing further evidence that mutations in the gene for the basolateral chloride channel CLC-Kb are the molecular basis of classic Bartter syndrome. Interestingly, the phenotype elicited by CLCNKB mutations occasionally includes HPS/aBS, as well as a Gitelman-like phenotype.

Amino Acid Sequence↗