Abstract
Background
Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited condition associated primarily with
PKD1
and
PKD2
genes. However, ADPKD patients in Latin America have ...had limited access to comprehensive care. The ProPKD score predicts the likelihood of kidney failure before the age of 60. This study aimed to describe the clinical and genetic characteristics of Chilean ADPKD patients and assess the ProPKD score.
Methods
We enrolled 40 ADPKD probands and 122 relatives from different centers. Genetic analysis of
PKD1
and
PKD2
genes was performed by combining direct and next-generation sequencing. Pathogenicity was determined using bioinformatic tools. ProPKD scores were calculated based on clinical and genetic data.
Results
ADPKD probands were diagnosed at a median age of 35 years. Pathogenic, likely pathogenic, or uncertain significance variants were identified in 38/40 pedigrees, with 89% involving
PKD1
and 11% involving
PKD2
variants. Among the identified variants, 62% were novel. Patients with
PKD1
truncating variants had a more severe disease course, reaching kidney failure by a median age of 48.5 years. ProPKD scores were assessed in 72 individuals, stratifying them into high-, intermediate-, or low-risk categories and the median ages for kidney failure were 45, 49, and 52 years, respectively (log-rank
p
= 0.001).
Conclusion
This study provides valuable insights into the clinical and genetic profiles of ADPKD patients in Chile. ADPKD poses a significant public health concern, warranting improvements in diagnosis and treatment. The use of the ProPKD score to predict disease progression should be further explored to enhance patient care and management.
Understanding the processes that give rise to genomic variability in extant species is an active area of research within evolutionary biology. With the availability of whole genome sequences, it is ...possible to quantify different forms of variability such as variation in gene copy number, which has been described as an important source of genetic variability and in consequence of phenotypic variability. Most of the research on this topic has been focused on understanding the biological significance of gene duplication, and less attention has been given to the evolutionary role of gene loss. Gremlin 2 is a member of the DAN gene family and plays a significant role in tooth development by blocking the ligand-signaling pathway of BMP2 and BMP4. The goal of this study was to investigate the evolutionary history of gremlin 2 in cetartiodactyl mammals, a group that possesses highly divergent teeth morphology. Results from our analyses indicate that gremlin 2 has experienced a mixture of gene loss, gene duplication, and rate acceleration. Although the last common ancestor of cetartiodactyls possessed a single gene copy, pigs and camels are the only cetartiodactyl groups that have retained gremlin 2. According to the phyletic distribution of this gene and synteny analyses, we propose that gremlin 2 was lost in the common ancestor of ruminants and cetaceans between 56.3 and 63.5 million years ago as a product of a chromosomal rearrangement. Our analyses also indicate that the rate of evolution of gremlin 2 has been accelerated in the two groups that have retained this gene. Additionally, the lack of this gene could explain the high diversity of teeth among cetartiodactyl mammals; specifically, the presence of this gene could act as a biological constraint. Thus, our results support the notions that gene loss is a way to increase phenotypic diversity and that gremlin 2 is a dispensable gene, at least in cetartiodactyl mammals.
Background
Genetic diagnosis of autosomal recessive polycystic kidney disease (ARPKD) is challenging due to the length and allelic heterogeneity of the
PKHD1
gene. Mutations appear to be clustered at ...specific exons, depending on the geographic origin of the patient. We aimed to identify the
PKHD1
exons most likely mutated in Spanish ARPKD patients.
Methods
Mutation analysis was performed in 50 ARPKD probands and nine ARPKD-suspicious patients by sequencing
PKHD1
exons arranged by their reported mutation frequency. Haplotypes containing the most frequent mutations were analyzed. Other PKD genes (
HNF1B, PKD1, PKD2
) were sequenced in
PKHD1
-negative cases.
Results
Thirty-six different mutations (concentrated in 24
PKHD1
exons) were detected, giving a mutation detection rate of 86 %. The screening of five exons (58, 32, 34, 36, 37) yielded a 54 % chance of detecting one mutation; the screening of nine additional exons (3, 9, 39, 61, 5, 22, 26, 41, 57) increased the chance to 76 %. The c.9689delA mutation was present in 17 (34 %) patients, all of whom shared the same haplotype. Two
HNF1B
mutations and one
PKD1
variant were detected in negative cases.
Conclusions
Establishing a
PKHD1
exon mutation profile in a specific population and starting the analysis with the most likely mutated exons might significantly enhance the efficacy of genetic testing in ARPKD. Analysis of other PKD genes might be considered, especially in suspicious cases.
Background
Hemolytic uremic syndrome secondary to Shiga-toxin-producing
Escherichia coli
infection (STEC-HUS) generally shows a favorable outcome. Few cases develop extra-renal complications, since ...neurological involvement is an important cause of morbidity and mortality. The role of complement in STEC-HUS has been recently highlighted, and the use of eculizumab in severe cases has been communicated. HUS results from environmental and genetic factors, but the simultaneous occurrence of STEC and complement mutations remains undetermined.
Methods
A pediatric case with severe STEC-HUS carrying
CFH
mutations, with favorable response to eculizumab is analyzed.
Results
STEC-HUS was diagnosed in a 4-year-old girl with classic HUS, including low C3. Peritoneal dialysis was started due to hypertension, oligoanuria, and pleural effusion. She evolved with generalized tonic–clonic seizures and required mechanical ventilation. MRI reported multiple supra- and infratentorial ischemic lesions with laminar/striatal cortical necrosis and leukoencephalopathy. After two eculizumab doses, a significative stabilization in diuresis, blood pressure, creatinine, and C3 was achieved. At the third week, episodes of massive digestive bleeding and a life-threatening condition required a colectomy thus preserving the ileocecal valve. Due to atypical evolution, a genetic study was considered, identifying two heterozygous variants (CFH S1191L/V1197A).
Conclusion
STEC-HUS in patients with a genetic predisposition has been previously reported, but the low frequency of occurrence makes it a rare disease. As in the present case, patients with atypical course might benefit from genetic analysis to evaluate early eculizumab initiation and to better understand its phenotype.
Graphical abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
Background
Nephrocalcinosis (NC) is characterized by an excessive accumulation of calcium deposits in the kidneys. In children, it is often incidentally discovered with an uncertain prognosis.
...Case-diagnosis/treatment
A 3-month-old girl suspected to have a milk protein allergy underwent an ultrasound that revealed increased echogenicity in the kidney pyramids suggestive of medullary NC. At the age of 18 months, imaging findings revealed not only hyperechogenicity in the medulla but also in the cortex. Over the course of a long follow-up, her kidneys maintained size within the upper limits but showed an increase by age 7. Genetic analysis identified
PKHD1
variants, which required structural predictive tools to guide clinical diagnosis. Until the age of 7, her kidney function has remained intact; however, her prognosis is uncertain.
Conclusions
NC in newborns is a rare condition, but its incidence is rising. Recurrent urinary infections or kidney stones may lead to kidney failure. A proactive approach in sporadic NC enables an early diagnosis to orientate clinical supervision and facilitates counseling to support family planning decisions.
The current therapeutic strategy for the treatment of chronic kidney diseases only ameliorates disease progression. During renal injury, developmental genes are re-expressed and could be potential ...therapeutic targets. Among those genes reactivated in the adult damaged kidney, Gremlin is of particular relevance since recent data suggest that it could be a mediator of diabetic nephropathy and other progressive renal diseases. Earlier studies have shown that Gremlin is upregulated in trans-differentiated renal proximal tubular cells and in several chronic kidney diseases associated with fibrosis. However, not much was known about the mechanisms by which Gremlin acts in renal pathophysiology. The role of Gremlin as a bone morphogenetic protein antagonist has clearly been demonstrated in organogenesis and in fibrotic-related disorders. Gremlin binds to vascular endothelial growth factor receptor 2 (VEGFR2) in endothelial and tubular epithelial cells. Activation of the Gremlin-VEGFR2 axis was found in several human nephropathies. We have recently described that Gremlin activates the VEGFR2 signaling pathway in the kidney, eliciting a downstream mechanism linked to renal inflammatory response. Gremlin deletion improves experimental renal damage, diminishing fibrosis. Overall, the available data identify the Gremlin-VEGFR2 axis as a novel therapeutic target for kidney inflammation and fibrosis and provide a rationale for unveiling new concepts to investigate in several clinical conditions.
Background
Anemia exhibits complex causation mechanisms and genetic heterogeneity. Some cases result in poor outcomes with multisystemic dysfunction, including renal tubulopathy. Early diagnosis is ...crucial to improve management.
Case–diagnosis/treatment
A 21-month-old female patient was admitted with severe anemia. Persistent neutropenia and dysplastic signs suggested myelodysplastic syndrome, but targeted gene panel results were negative. After multiple transfusions, spontaneous hematologic recovery was observed. At 4 years old, she presented failure to thrive, renal Fanconi syndrome, and severe metabolic acidosis. Differential diagnosis included Pearson syndrome (PS), a life-threatening condition associated with mitochondrial DNA (mtDNA), featuring anemia and pancreatic insufficiency. Further analysis revealed a ~ 7.5 kb mtDNA deletion. Until the age of 5, supportive care has been provided, without pancreatic insufficiency.
Conclusions
This PS case highlights the importance of genetic testing, even in the absence of typical features. Understanding the nature of mitochondrial disorders enables treatment tailoring and counseling about the prognosis.
The epithelial sodium channel (ENaC) is a candidate gene associated with the development of essential hypertension. A potentially polymorphic repetitive region (GT dinucleotide short tandem repeat ...STR) was identified in intron 8 of β-ENaC gene (SCNN1B). The aim of this study was to identify the prevalence and distribution of a polymorphic GT-STR in SCNN1B in Chilean essential hypertensive (EH) patients and to analyze the correlation between the different genotypes with plasma renin activity (PRA) and serum aldosterone (SA), and furthermore, to evaluate the β-ENaC gene expression in vitro.
We studied 133 patients with EH and 69 normotensive (NT). In both EH and NT subjects we measured PRA, SA, urine sodium, and genotyped them according to the GT-STR length using sequencing analysis. We detected 11, 13 and 14 GT alleles in EH and NT subjects. Both groups were classified according to genotype: 14/14, 14/13, 13/13, 13/11, and 11/11. Influence of the GT-STR on β-ENaC minigene expression was evaluated by real-time polymerase chain reaction.
In EH, PRA decreased with the length of the STR region 11/13, 1.40 ± 0.69; 13/13, 1.16 ± 0.61; 13/14, 0.90 ± 0.56; 14/14, 0.32 ± 0.09 ng/mL/h;
P < .01. Likewise, PRA in patients with EH with 14/14 or 14/13 genotypes were lower than EH with 13/13 or 13/11 genotypes (0.77 ± 0.5
v 1.24 ± 0.6 ng/mL/h;
P < .01). Real-time polymerase chain reaction demonstrated an increased β-ENaC expression in minigenes containing 14 GT-STR.
We have identified a polymorphic GT-STR in the β-ENaC gene, which is present in the EH and NT Chilean population. Biochemical analysis showed a possible linkage between this polymorphic region and low renin hypertension. The in vitro assay suggests that GT-STR could regulate the β-ENaC expression.
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