Genetic variants of the COL4A3, COL4A4, and COL4A5 genes contribute to thinned glomerular basement membrane lesions in sporadic IgA nephropathy patients
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ABSTRACT:
PROVIDER: EGAS00001006519 | EGA |
REPOSITORIES: EGA
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Project description:Background: Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the central nervous system that leads to progressive loss of upper and lower motor neurons. Most cases are sporadic and of unknown aetiology. In this study, we screened 71 patients with sporadic ALS for the presence of DNA copy number variations, in order to identify novel candidate disease genes. Methods: We have used sub-megabase resolution BAC array comparative genomic hybridisation to detect genomic imbalances in our ALS patient cohort. In order to distinguish phenotypically neutral copy number variations occurring frequently in the normal population from disease-associated aberrations, we screened our results against both the Database of Genomic Variants and a reference data set of approximately 700 normal individuals and probands with other disorders analysed in our laboratory. Aberrations with potential relevance for disease aetiology were verified by oligo array CGH. Findings: In 71 patients with sporadic ALS, we identified a total of six duplications and seven deletions that scored above our threshold. Twelve of these thirteen variations were smaller than 1Mb. Seven were observed exclusively in ALS patients and thus likely play causal roles in the disorder. Analysis of these regions highlighted, for example, the SLC1A7 (EAAT5) glutamate transporter and the kinesin family member KIF9 as good positional and functional candidate genes for ALS. Interpretation: Non-polymorphic sub-microscopic duplications and deletions observable by array CGH are frequent in patients with sporadic ALS. Analysis of such aberrations serves as an excellent starting point in deciphering the aetiology of this complex disease. Keywords: array CGH A cohort of 71 ALS patients was analysed by means of a submegabase resolution BAC array. No replicates were included. Experiments were done without dye swap.
2008-12-24 | E-GEOD-7950 | biostudies-arrayexpress
Project description:Background: Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the central nervous system that leads to progressive loss of upper and lower motor neurons. Most cases are sporadic and of unknown aetiology. In this study, we screened 71 patients with sporadic ALS for the presence of DNA copy number variations, in order to identify novel candidate disease genes. Methods: We have used sub-megabase resolution BAC array comparative genomic hybridisation to detect genomic imbalances in our ALS patient cohort. In order to distinguish phenotypically neutral copy number variations occurring frequently in the normal population from disease-associated aberrations, we screened our results against both the Database of Genomic Variants and a reference data set of approximately 700 normal individuals and probands with other disorders analysed in our laboratory. Aberrations with potential relevance for disease aetiology were verified by oligo array CGH. Findings: In 71 patients with sporadic ALS, we identified a total of six duplications and seven deletions that scored above our threshold. Twelve of these thirteen variations were smaller than 1Mb. Seven were observed exclusively in ALS patients and thus likely play causal roles in the disorder. Analysis of these regions highlighted, for example, the SLC1A7 (EAAT5) glutamate transporter and the kinesin family member KIF9 as good positional and functional candidate genes for ALS. Interpretation: Non-polymorphic sub-microscopic duplications and deletions observable by array CGH are frequent in patients with sporadic ALS. Analysis of such aberrations serves as an excellent starting point in deciphering the aetiology of this complex disease. Keywords: array CGH
2008-12-25 | GSE7950 | GEO
Project description:BackgroundThinned glomerular basement membrane (tGBM) lesions are not uncommon in IgA nephropathy (IgAN). Type IV collagen-built of α 3, α 4, and α 5 chains, encoded by COL4A3 / COL4A4 / COL4A5 genes-is the major component of glomerular basement membrane (GBM). In recent years, mutations in type IV collagen-encoding genes were also reported in patients with a histologic diagnosis of FSGS. Pathogenic COL4A3 / COL4A4 / COL4A5 variants were recently identified in familial cases of IgAN, but the contribution of these variants to sporadic IgAN is still unclear.MethodsWe compared 161 patients with sporadic IgAN with tGBM lesions (IgAN-tGBM) to matched patients with IgAN without tGBM lesions and matched patients with thin basement membrane nephropathy (TBMN). Variants of COL4A3 / COL4A4 / COL4A5 genes were screened and evaluated after whole-exome sequencing. GBM thickness was measured, and levels of circulating galactose-deficient IgA1 (Gd-IgA1) were assessed by ELISA.ResultsThe patients with IgAN-tGBM manifested milder disease than did patients with IgAN without tGBM but had more severe features than the patients with TBMN. Exome sequence analysis of the 122 patients with IgAN-tGBM identified 37 diagnostic variants of the COL4A3 / COL4A4 / COL4A5 genes among 38 patients (31.1%). Furthermore, patients with IgAN-tGBM who had diagnostic variants had higher proportions of GBM thickness <250 nm and milder glomerular injury, whereas patients with IgAN-tGBM who did not have diagnostic variants showed more characteristic features of IgAN, including higher intensity of glomerular IgA deposits and elevated Gd-IgA1 levels. These findings suggest different mechanisms in patients with versus without diagnostic variants of these collagen genes.ConclusionsCOL4A3 / COL4A4 / COL4A5 variant detection is essential in evaluating patients with sporadic IgAN with tGBM lesions.
| S-EPMC10101589 | biostudies-literature
Project description:Genomic DNA from sporadic breast tumours was isolated and analysed using array CGH. The NKI 1MB BAC/PAC micro array was used to identify chromosomal aberrations of all tumours. Keywords: sporadic breast tumour, CGH
2010-07-05 | GSE9114 | GEO
Project description:Sporadic Amyotrophic Lateral Sclerosis Study
| PRJNA310034 | ENA
Project description:In this study, the investigators compared and evaluated the clinicopathological and oncological characteristics of sporadic colorectal cancer (CRC) in young adults without genetic mutations associated with hereditary CRC syndrome and sporadic CRC in elderly individuals.
| 2753068 | ecrin-mdr-crc
Project description:Genomic DNA from sporadic breast tumours was isolated and analysed using array CGH. The NKI 1MB BAC/PAC micro array was used to identify chromosomal aberrations of all tumours. Other profiles are located at: GSE9114 Keywords: sporadic breast tumour, CGH.
2010-10-26 | GSE22401 | GEO
Project description:Rationale: Idiopathic interstitial pneumonia (IIP) and its’ familial variants are progressive and largely untreatable disorders with poorly understood molecular mechanisms. Both the genetics and the histologic type of IIP play a role in understanding the etiology and pathogenesis of interstitial lung disease, but transcriptional signatures of these subtypes are unknown. Objectives: To evaluate gene expression in the lung tissue from patients with usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP) that were either familial or non-familial in origin and compare them to gene expression from normal lung parenchyma. Methods: We profiled RNA from lungs of 16 patients with sporadic IIP, 10 with familial IIP, and 9 normal controls on a whole human genome oligonucleotide microarray. Results: Significant transcriptional differences exist in familial and sporadic IIPs. The genes distinguishing the genetic subtypes belong to the same functional categories as transcripts that distinguish IIP from normal samples. Relevant categories include chemokines and growth factors and their receptors, complement components, genes associated with cell proliferation and death, and genes in the Wnt pathway. Keywords: disease state analysis
2006-10-01 | GSE5774 | GEO