Mutations in the COL4A5 gene cause X-linked Alport syndrome (XLAS). Understanding the correlation between clinical manifestations and the underlying mutations adds prognostic value to genetic testing, which is increasingly available. Our aim was to determine the association between genotype and phenotype in 681 affected male participants with XLAS from 175 US families. Hearing loss and ocular changes were present in 67 and 30% of participants, respectively. Average age of participants at onset of ESRD was 37 years for those with missense mutations, 28 years for those with splice-site mutations, and 25 years for those with truncating mutations (P Ͻ 0.0001). We demonstrated a strong relationship between mutation position and age at onset of ESRD, with younger age at onset of ESRD associated with mutations at the 5Ј end of the gene (hazard ratio 0.766 [95% confidence interval 0.694 to 0.846] per 1000 bp toward the 3Ј end; P Ͻ 0.0001). Affected participants with splice mutations or truncating mutations each had two-fold greater odds of developing eye problems than those with missense mutations; development of hearing impairment showed a similar trend. Hearing loss and ocular changes associated with mutations located closer to the 5Ј end of the gene. These strong genotype-phenotype correlations could potentially help in the evaluation and counseling of US families with XLAS.
We identified the human ortholog of soluble adenylyl cyclase (hsAC) in a locus linked to familial absorptive hypercalciuria and cloned it from a human cDNA library. hsAC transcripts were expressed in multiple tissues using RT-PCR and RNA blotting. RNA blot analysis revealed a predominant 5.1-kb band in a multiple human tissue blot, but three splice transcript variants were detected using RT-PCR and confirmed by performing sequence analysis. Immunoblot analysis showed 190- and 80-kDa bands in multiple human cell lines from gut, renal, and bone origins in both cytosol and membrane fractions, including Caco-2 colorectal adenocarcinomas, HEK-293 cells, HOS cells, and primary human osteoblasts, as well as in vitro induced osteoclast-like cells. The specificity of the antiserum was verified by peptide blocking and reduction using sequence-specific small interfering RNA. Confocal immunofluorescence cytochemistry localized hsAC primarily in cytoplasm, but some labeling was observed in the nucleus and the plasma membrane. Cytoplasmic hsAC colocalized with microtubules but not with microfilaments. To test the function of hsAC, four constructs containing catalytic domains I and II (aa 1-802), catalytic domain II (aa 231-802), noncatalytic domain (aa 648-1,610), and full-length protein (aa 1-1,610) were expressed in Sf9 insect cells. Only catalytic domains I and II or full-length proteins showed adenylyl cyclase activity. Mg(2+), Mn(2+), and Ca(2+) all increased adenylyl cyclase activity in a dose-dependent manner. While hsAC had a minimal response to HCO(3)(-) in the absence of divalent cations, HCO(3)(-) robustly stimulated Mg(2+)-bound hsAC but inhibited Mn(2+)-bound hsAC in a dose-dependent manner. In summary, hsAC is a divalent cation and HCO(3)(-) sensor, and its HCO(3)(-) sensitivity is modulated by divalent cations.
Modifier loci in the genetic background are important factors in inter- and intrafamilial variability in the phenotypic expression of PKD1. The extreme intrafamilial phenotype differences are consistent with the hypothesis that one or a few modifier genes have a major effect on the progression and severity of PKD1.
SummaryBackground and objectives The purpose of this study was to determine whether glomerular hyperfiltration (GH) occurring early in autosomal dominant polycystic kidney disease (ADPKD) is indicative of more rapid disease progression in children.Design, setting, participants, & measurements One hundred eighty children with ADPKD (ages 4 to 18 years) with normal renal function were examined by renal ultrasound. Renal volume was calculated using a standard formula for a modified ellipsoid. Creatinine clearance was calculated from serum creatinine and 24-hour urine creatinine. GH was defined as creatinine clearance Ն140 ml/min per 1.73 m 2 .Results Thirty-two children had GH (mean age 11.4 Ϯ 3.6 years) and 148 had normal renal function (mean age 10.8 Ϯ 3.9 years). Patients with GH at baseline demonstrated an increased rate of total renal volume growth (: rate of change ϭ ϩ19.3 Ϯ 10.8 cm 3 /year) over 5 years compared with those without GH at baseline ( ϭ Ϫ4.3 Ϯ 7.7 cm 3 /year), P ϭ 0.008. Those with GH at baseline experienced a faster decline in creatinine clearance in subsequent years ( ϭ Ϫ5.0 Ϯ 0.8 ml/min per 1.73 m 2 per year) compared with those without GH at baseline ( ϭ ϩ1.0 Ϯ 0.4 ml/min per 1.73 m 2 per year), P Ͻ 0.0001. ConclusionsThis study revealed that occurrence of GH in ADPKD children is associated with a significantly faster decline in renal function and higher rate of kidney enlargement over time. GH combined with the increased renal volume may therefore be used as an early marker for a more severe progression of ADPKD in children.
Background: This study evaluates the prevalence of cardiovascular events in autosomal dominant polycystic kidney disease (ADPKD) patients. Methods: We distributed surveys to 1,439 subjects from our ADPKD research database. In total, 426 subjects completed and returned surveys; 7 of these were from children and were excluded from the study. Results: The patients who responded were female (63.2%), nonHispanic (88.1%) and white (93.6%). The mean age of the total group was 53.2 ± 13.7 years; 82.8% had a family history of ADPKD and 32.5% had reached end-stage renal disease (ESRD). With respect to cardiovascular risk factors, 86.6% were hypertensive with a mean age at diagnosis of 36.9 ± 12.9 years and hypertension was significantly more prevalent in males. In addition, 19.6% of the subjects were obese, 20.8% were smokers, 8.7% had diabetes, 45.7% had high cholesterol and 17.8% were sedentary. The most prevalent self-reported cardiovascular events were arrhythmias (25.9%), evidence of peripheral vascular disease (16.5%), heart valve problems (14.4%), cardiac enlargement (9.5%), stroke or cerebral bleeding (7.5%), myocardial infarction (6%) and brain aneurysm (5.0%). The most commonly used antihypertensive medications were renin-angiotensin inhibitors used by 75% of ADPKD patients.Older ADPKD patients and those at ESRD had a significantly higher incidence of cardiovascular events. Conclusion: These findings support the high prevalence of cardiovascular risk factors and events in ADPKD patients which contribute to a greater mortality risk. Due to the prevalence of cardiovascular risk factors in the ADPKD population, early diagnosis and clinical intervention are recommended.
Background-At the University of Colorado Health Sciences Center, approximately 10% of patients with autosomal dominant polycystic kidney disease (ADPKD) on detailed questioning gave no family history of ADPKD. There are several explanations for this observation including occurrence of a de novo pathogenic sequence variant or extreme phenotypic variability. In order to confirm de novo sequence variants we have undertaken a clinical and genetic screening of affected offspring and their parents.
Absorptive hypercalciuria (AH) is a kidney stone-forming condition frequently complicated by bone loss. Previously, we mapped the locus for an inherited form of AH to chromosome 1q23.3-q24. We have sequenced a putative gene (subsequently shown by others to be homologous with the rat soluble adenylate cyclase gene) in this region in 12 unrelated Caucasian AH patients. Eighteen base substitutions were identified in the soluble adenylate cyclase human homolog gene. All sequence variations were further evaluated in 3-68 additional unrelated AH patients and 19-132 normal subjects, and 1 additional base substitution was identified. Six of the identified sequence variations occurred with increased frequency in the AH population and tracked with the AH phenotype in AH families. Calculated odds ratios showed that the occurrence of any 4 of these individual base substitutions was associated with a 2.2- to 3.5-fold increase in estimated risk for AH (P < 0.02). In addition, 1 or more base changes was associated with a lower L2-L4 vertebral bone density. Sequence analysis of 3 other genes within the AH linkage interval showed no difference in the distribution of sequence variations between AH and normal populations. This is the first description of a specific gene defect associated with AH.
Absorptive hypercalciuria (AH), a common cause of kidney stones, is due to intestinal hyperabsorption of calcium. The presence of a family history of nephrolithiasis, in about half of the affected individuals studied indicates that an inherited genetic defect is one likely cause of AH. Although it is known that intestinal calcium absorption is regulated by a number of factors, the molecular biological basis for the increased calcium absorption in AH is unknown. This study was designed to determine the chromosomal locus of the gene defect linked to the AH phenotype in three families with a severe form of AH. Three kindreds were evaluated in a systematic autosomal genome-wide linkage analysis study. The AH phenotype, characterized by hyperabsorption of calcium and hypercalciuria, was linked to only one chromosomal locus, 1q23.3-q24. A 2-point logarithm of odds score of 3.3 was obtained with markers D1S318 and D1S196 at a recombination frequency of theta = 0. Nonparametric multipoint linkage analysis yielded a peak nonparametric linkage Z(all)-score of 12.7, P = 6 x 10(-6) Analysis of key recombinants within the families studied localized the gene to a 4.3-megabase region between markers D1S2681 (centromere) and D1S2815. A trait associated with intestinal hyperabsorption of calcium in a severe form of absorptive hypercalciuria has been mapped to chromosome 1q23.3-q24.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.