-
Molecular Vision 2020The aim of the present work is the molecular diagnosis of three patients with deafness and retinal degeneration.
PURPOSE
The aim of the present work is the molecular diagnosis of three patients with deafness and retinal degeneration.
METHODS
Three patients from two unrelated families were initially analyzed with custom gene panels for Usher genes, non-syndromic hearing loss, or inherited syndromic retinopathies and further investigated by means of clinical or whole exome sequencing.
RESULTS
The study allowed us to detect likely pathogenic variants in , a gene typically involved in peroxisomal biogenesis disorders (PBDs). Beside deaf-blindness, both families showed additional features: Siblings from Family 1 showed enamel alteration and abnormal peroxisome. In addition, the brother had mild neurodevelopmental delay and nephrolithiasis. The case II:1 from Family 2 showed intellectual disability, enamel alteration, and dysmorphism.
CONCLUSIONS
We have reported three new cases with pathogenic variants in presenting with milder forms of the Zellweger spectrum disorders (ZSD). The three cases showed distinct clinical features. Thus, expanding the phenotypic spectrum of PBDs and ascertaining exome sequencing is an effective strategy for an accurate diagnosis of clinically overlapping and genetically heterogeneous disorders such as deafness-blindness association.
Topics: ATPases Associated with Diverse Cellular Activities; Adult; Child; Craniofacial Abnormalities; Dental Enamel; Female; Hearing Loss, Sensorineural; Humans; Intellectual Disability; Male; Mutation; Nephrolithiasis; Neurodevelopmental Disorders; Pedigree; Peroxisomes; Retinitis Pigmentosa; Exome Sequencing; Zellweger Syndrome
PubMed: 32214787
DOI: No ID Found -
Genetics in Medicine : Official Journal... Jun 2020A Renal Genetics Clinic (RGC) was established to optimize diagnostic testing, facilitate genetic counseling, and direct clinical management.
PURPOSE
A Renal Genetics Clinic (RGC) was established to optimize diagnostic testing, facilitate genetic counseling, and direct clinical management.
METHODS
Retrospective review of patients seen over a two-year period in the RGC.
RESULTS
One hundred eleven patients (mean age: 39.9 years) were referred to the RGC: 65 for genetic evaluation, 19 for management of a known genetic disease, and 18 healthy living kidney donors (LKDs) and their 9 related transplant candidates for screening. Forty-three patients underwent genetic testing with a diagnosis in 60% of patients including 9 with Alport syndrome, 7 with autosomal dominant polycystic kidney disease (ADPKD), 2 with genetic focal segmental glomerulosclerosis (FSGS), 2 with PAX2-mediated CAKUT, and 1 each with autosomal recessive polycystic kidney disease (ARPKD), Dent, Frasier, Gordon, Gitelman, and Zellweger syndromes. Four of 18 LKDs were referred only for APOL1 screening. For the remaining 14 LKDs, their transplant candidates were first tested to establish a genetic diagnosis. Five LKDs tested negative for the familial genetic variant, four were positive for their familial variant. In five transplant candidates, a genetic variant could not be identified.
CONCLUSION
An RGC that includes genetic counseling enhances care of renal patients by improving diagnosis, directing management, affording presymptomatic family focused genetic counseling, and assisting patients and LKDs to make informed decisions.
Topics: Adult; Apolipoprotein L1; Genetic Testing; Humans; Kidney; Mass Screening; Polycystic Kidney, Autosomal Dominant; Retrospective Studies
PubMed: 32203225
DOI: 10.1038/s41436-020-0772-y -
Histochemistry and Cell Biology May 2020Peroxisomes are ubiquitous organelles formed by peroxisome biogenesis (PB). During PB, peroxisomal matrix proteins harboring a peroxisome targeting signal (PTS) are...
Peroxisomes are ubiquitous organelles formed by peroxisome biogenesis (PB). During PB, peroxisomal matrix proteins harboring a peroxisome targeting signal (PTS) are imported inside peroxisomes by peroxins, encoded by PEX genes. Genetic alterations in PEX genes lead to a spectrum of incurable diseases called Zellweger spectrum disorders (ZSD). In vitro drug screening is part of the quest for a cure in ZSD by restoring PB in ZSD cell models. In vitro PB evaluation is commonly achieved by immunofluorescent staining or transient peroxisome fluorescent reporter expression. Both techniques have several drawbacks (cost, time-consuming technique, etc.) which we overcame by developing a third-generation lentiviral transfer plasmid expressing an enhanced green fluorescent protein fused to PTS1 (eGFP-PTS1). By eGFP-PTS1 lentiviral transduction, we quantified PB and peroxisome motility in ZSD and control mouse and human fibroblasts. We confirmed the stable eGFP-PTS1 expression along cell passages. eGFP signal analysis distinguished ZSD from control eGFP-PTS1-transduced cells. Live eGFP-PTS1 transduced cells imaging quantified peroxisomes motility. In conclusion, we developed a lentiviral transfer plasmid allowing stable eGFP-PTS1 expression to study PB (deposited on Addgene: #133282). This tool meets the needs for in vitro PB evaluation and ZSD drug discovery.
Topics: Animals; Cells, Cultured; Fibroblasts; Green Fluorescent Proteins; Humans; Mice; Peroxisomal Targeting Signals; Peroxisomes; Zellweger Syndrome
PubMed: 32124009
DOI: 10.1007/s00418-020-01855-z -
International Journal of Pediatrics &... Dec 2019
PubMed: 31890844
DOI: 10.1016/j.ijpam.2019.11.002 -
G3 (Bethesda, Md.) Jan 2020Peroxisomes are subcellular organelles that are essential for proper function of eukaryotic cells. In addition to being the sites of a variety of oxidative reactions,...
Peroxisomes are subcellular organelles that are essential for proper function of eukaryotic cells. In addition to being the sites of a variety of oxidative reactions, they are crucial regulators of lipid metabolism. Peroxisome loss or dysfunction leads to multi-system diseases in humans that strongly affect the nervous system. In order to identify previously unidentified genes and mechanisms that impact peroxisomes, we conducted a genetic screen on a collection of lethal mutations on the chromosome in Using the number, size and morphology of GFP tagged peroxisomes as a readout, we screened for mutations that altered peroxisomes based on clonal analysis and confocal microscopy. From this screen, we identified eighteen genes that cause increases in peroxisome number or altered morphology when mutated. We examined the human homologs of these genes and found that they are involved in a diverse array of cellular processes. Interestingly, the human homologs from the -chromosome collection are under selective constraint in human populations and are good candidate genes particularly for dominant genetic disease. This screening approach for peroxisome defects allows identification of novel genes that impact peroxisomes in a multicellular organism and is a valuable platform to discover genes potentially involved in dominant disease that could affect peroxisomes.
Topics: Animals; Drosophila melanogaster; Genes, Insect; Humans; Mutation; Peroxisomes; Sequence Homology, Nucleic Acid; X Chromosome; Zellweger Syndrome
PubMed: 31767637
DOI: 10.1534/g3.119.400803 -
Journal of Applied Genetics Feb 2020Zellweger spectrum disorders (ZSD) constitute a group of rare autosomal recessive disorders characterized by a defect in peroxisome biogenesis due to mutations in one of...
Zellweger spectrum disorders (ZSD) constitute a group of rare autosomal recessive disorders characterized by a defect in peroxisome biogenesis due to mutations in one of 13 PEX genes. The broad clinical heterogeneity especially in late-onset presenting patients and a mild phenotype complicates and delays the diagnostic process. Here, we report a case of mild ZSD, due to novel PEX1 variants. The patient presented with an early hearing loss, bilateral cataracts, and leukodystrophy on magnetic resonance (MR) images. Normal results of serum very-long-chain fatty acids (VLCFA) and phytanic acid were found. Molecular diagnostics were performed to uncover the etiology of the clinical phenotype. Using whole exome sequencing, there have been found two variants in the PEX1 gene-c.3450T>A (p.Cys1150*) and c.1769T>C (p.Leu590Pro). VLCFA measurement in skin fibroblasts and C26:0-lysoPC in dried blood spot therefore was performed. Both results were in line with the diagnosis of ZSD. To conclude, normal results of routine serum VLCFA and branched-chain fatty acid measurement do not exclude mild forms of ZSD. The investigation of C26:0-lysoPC should be included in the diagnostic work-up in patients with cataract, hearing loss, and leukodystrophy on MR images suspected to suffer from ZSD.
Topics: ATPases Associated with Diverse Cellular Activities; Adolescent; Biomarkers; Brain; Child; Child, Preschool; DNA Mutational Analysis; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Humans; Infant; Magnetic Resonance Imaging; Male; Membrane Proteins; Phenotype; Severity of Illness Index; Symptom Assessment; Young Adult; Zellweger Syndrome
PubMed: 31628608
DOI: 10.1007/s13353-019-00523-w -
European Heart Journal Jan 2020
Topics: Cardiology; Chronic Disease; Coronary Artery Disease; Diagnostic Techniques, Cardiovascular; Disease Management; Europe; Humans; Societies, Medical; Syndrome
PubMed: 31504439
DOI: 10.1093/eurheartj/ehz425 -
European Heart Journal. Case Reports Sep 2019Acute coronary syndrome (ACS) can be a life-threatening condition. However, identification of patients with ACS can be challenging, especially among women, and clinical...
BACKGROUND
Acute coronary syndrome (ACS) can be a life-threatening condition. However, identification of patients with ACS can be challenging, especially among women, and clinical presentation can often overlap with other medical entities.
CASE SUMMARY
A 61-year-old woman with a history of stable bronchial asthma presented with worsening dyspnoea for spiroergometry. During bicycle exercise testing, she developed acute chest pain and her electrocardiogram showed significant ST-segment elevations. High-sensitivity cardiac troponin was elevated and a coronary angiography was performed showing normal coronary arteries. Cardiac magnetic resonance imaging showed no signs of myocardial infarction, myocarditis or Takotsubo cardiomyopathy but the incidental finding of a giant hiatal hernia impeding the filling of the left atrium. The giant hernia was surgically corrected, and the patient's exertional dyspnoea fully relieved during follow-up.
DISCUSSION
Hiatal hernia might compress cardiac structures, cause exertional dyspnoea and mimic ST-elevation myocardial infarction. 10.1093/ehjcr/ytz138_audio1 ytz138_audio1 6074443146001.
PubMed: 31425572
DOI: 10.1093/ehjcr/ytz138 -
International Journal of Molecular... Aug 2019Peroxisome biogenesis disorders (PBDs) are nontreatable hereditary diseases with a broad range of severity. Approximately 65% of patients are affected by mutations in... (Review)
Review
Peroxisome biogenesis disorders (PBDs) are nontreatable hereditary diseases with a broad range of severity. Approximately 65% of patients are affected by mutations in the peroxins Pex1 and Pex6. The proteins form the heteromeric Pex1/Pex6 complex, which is important for protein import into peroxisomes. To date, no structural data are available for this AAA+ ATPase complex. However, a wealth of information can be transferred from low-resolution structures of the yeast Pex1/Pex6 complex and homologous, well-characterized AAA+ ATPases. We review the abundant records of missense mutations described in PBD patients with the aim to classify and rationalize them by mapping them onto a homology model of the human Pex1/Pex6 complex. Several mutations concern functionally conserved residues that are implied in ATP hydrolysis and substrate processing. Contrary to fold destabilizing mutations, patients suffering from function-impairing mutations may not benefit from stabilizing agents, which have been reported as potential therapeutics for PBD patients.
Topics: ATPases Associated with Diverse Cellular Activities; Adenosine Triphosphate; Amino Acid Sequence; Animals; Humans; Membrane Proteins; Models, Molecular; Mutation, Missense; Peroxisomal Disorders; Protein Conformation; Protein Interaction Maps; Sequence Alignment
PubMed: 31374812
DOI: 10.3390/ijms20153756 -
Biochimica Et Biophysica Acta.... Oct 2019Zellweger spectrum disorders (ZSDs) are autosomal recessive diseases caused by defective peroxisome assembly. They constitute a clinical continuum from severe early...
Zellweger spectrum disorders (ZSDs) are autosomal recessive diseases caused by defective peroxisome assembly. They constitute a clinical continuum from severe early lethal to relatively milder presentations in adulthood. Liver disease is a prevalent symptom in ZSD patients. The underlying pathogenesis for the liver disease, however, is not fully understood. We report a hypomorphic ZSD mouse model, which is homozygous for Pex1-c.2531G>A (p.G844D), the equivalent of the most common pathogenic variant found in ZSD, and which predominantly presents with liver disease. After introducing the Pex1-G844D allele by knock-in, we characterized homozygous Pex1-G844D mice for survival, biochemical parameters, including peroxisomal and mitochondrial functions, organ histology, and developmental parameters. The first 20 post-natal days (P20) were critical for survival of homozygous Pex1-G844D mice (~20% survival rate). Lethality was likely due to a combination of cholestatic liver problems, liver dysfunction and caloric deficit, probably as a consequence of defective bile acid biosynthesis. Survival beyond P20 was nearly 100%, but surviving mice showed a marked delay in growth. Surviving mice showed similar hepatic problems as described for mild ZSD patients, including hepatomegaly, bile duct proliferation, liver fibrosis and mitochondrial alterations. Biochemical analyses of various tissues showed the absence of functional peroxisomes accompanied with aberrant levels of peroxisomal metabolites predominantly in the liver, while other tissues were relatively spared. ur findings show that homozygous Pex1-G844D mice have a predominant liver disease phenotype, mimicking the hepatic pathology of ZSD patients, and thus constitute a good model to study pathogenesis and treatment of liver disease in ZSD patients.
Topics: ATPases Associated with Diverse Cellular Activities; Alleles; Animals; Disease Models, Animal; Female; Fibroblasts; Humans; Liver; Liver Diseases; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Peroxisomes; Phenotype; Zellweger Syndrome
PubMed: 31207289
DOI: 10.1016/j.bbadis.2019.06.013