scholarly journals New familial cases of karyomegalic interstitial nephritis with mutations in the FAN1 gene

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Imen Rejeb ◽  
Mouna Jerbi ◽  
Houweyda Jilani ◽  
Hanène Gaied ◽  
Yasmina Elaribi ◽  
...  
Keyword(s):  
Interstitial Nephritis ◽  
Novel Mutation ◽  
Direct Sequencing ◽  
Tubular Epithelial Cell ◽  
Cell Nuclei ◽  
Progressive Decline ◽  
Coding Regions ◽  
Familial Cases ◽  
Damage Response ◽  
Dna Damage Response Pathway

Abstract Background Karyomegalic interstitial nephritis (KIN) is a rare disease entity first described by Burry in 1974. The term KIN was introduced by Mihatsch et al. in 1979. KIN is characterized by chronic tubulointerstitial nephritis associated with enlarged tubular epithelial cell nuclei, which leads to a progressive decline of renal function. The prevalence of this disease is less than 1% of all biopsies, and its pathogenesis is unclear. KIN results from mutations in FAN1 (FANCD2/FANCI-Associated Nuclease 1), a gene involved in the DNA damage response pathway, particularly in the kidney. In this study, we report two Tunisian consanguineous families with KIN caused by mutations in the FAN1 gene. Methods Direct sequencing of the coding regions and flanking intronic sequences of the FAN1 gene was performed in three affected members. Three prediction programs (Polyphen-2 software, SIFT, and MutationTaster) were used to predict the functional effect of the detected variations. Results Two causative frameshift variants in the FAN1 gene were identified in each family: The previously described frameshift mutation c.2616delA (p.Asp873ThrfsTer17) and a novel mutation c.2603delT (p.Leu868ArgfsTer22) classified as "pathogenic" according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Conclusion To our best knowledge, this is the first Tunisian study involving familial cases of KIN with mutations in the FAN1 gene. We hypothesize that these findings can expand the mutational spectrum of KIN and provide valuable information on the genetic cause of KIN.

scholarly journals New Familial Cases of Karyomegalic Interstitial Nephritis With Mutations in the FAN1 Gene

2020 ◽  
Author(s):  
Imen REJEB ◽  
Mouna Jerbi ◽  
Houweyda Jilani ◽  
Hanène Gaied ◽  
Yasmina Elaribi ◽  
...  
Keyword(s):  
Interstitial Nephritis ◽  
Dna Damage Response ◽  
Tubular Epithelial Cell ◽  
Disease Entity ◽  
Cell Nuclei ◽  
Novel Mutations ◽  
Progressive Decline ◽  
Familial Cases ◽  
Damage Response ◽  
Dna Damage Response Pathway

Abstract Karyomegalic interstitial nephritis (KIN) is a rare disease entity that was first described by Burry in 1974 and given this term by Mihatsch 1979 and al five years later. KIN is characterized by chronic tubulo-interstitial nephritis associated with enlarged tubular epithelial cell nuclei, which leads to progressive decline of renal function. The prevalence of this disease is less than 1% and its pathogenesis is unclear. KIN results from the mutation in the FAN 1 (FANCD2/FANCI-Associated Nuclease 1) gene, a gene involved in the DNA damage response pathway, particularly in the kidney. KIN seems to be rather multifactorial involving an environmental factor Ochratoxin A (OTA) but especially a genetic predisposition. In this article, we report 6 additional cases of KIN with histological evidence in 3 patients. Family clustering and differences in susceptibility to develop the nephropathy in spite of a high OTA contamination in all subjects show that there is a genetic susceptibility. So we completed our explorations by a genetic study. This study allowed us to identify novel mutations in the FAN1 gene in the affected members. To our best knowledge, this is the first Tunisian study involving familial cases of KIN with mutations on the FAN1 gene.

scholarly journals Identification of a novel mutation in the KITLG gene in a Chinese family with familial progressive hyper- and hypopigmentation

2020 ◽  
Author(s):  
Jianbo Wang ◽  
Weisheng Li ◽  
Naihui Zhou ◽  
Jingliu Liu ◽  
Shoumin Zhang ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Direct Sequencing ◽  
Three Dimensional ◽  
Chinese Family ◽  
The Novel ◽  
Exon 2 ◽  
Coding Regions ◽  
Pathogenicity Prediction ◽  
Café Au Lait Spots ◽  
Genetics And Genomics

Abstract Background: Familial progressive hyper- and hypopigmentation (FPHH, MIM 145250) is a rare hereditary skin disorder that is predominantly characterized by progressive, diffuse, partly blotchy hyperpigmented lesions intermingled with scattered hypopigmented spots, lentigines and sometimes Cafe-au-lait spots (CALs). Heterozygous mutations of the KIT ligand (KITLG, MIM 184745) gene are responsible for FPHH. To date, only eight KITLG mutations have been reported to be associated with FPHH, and no clear genotype-phenotype correlations have been established. This study aimed to identify the causative mutations in the KITLG gene in two Chinese FPHH patients.Methods: Direct sequencing of the coding regions of KITLG was performed. Pathogenicity prediction was performed using bioinformatics tools, including SIFT, Polyphen2, and SWISS-MODEL, and the results were further evaluated according to the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines.Results: The novel mutation c.104A>T (p.Asn35Ile) and the recurrent mutation c.101C>T (p.Thr34Ile) in KITLG were identified. As shown using SIFT and Polyphen-2 software, both mutations identified in this study were predicted to be detrimental variations. Three-dimensional protein structure modeling indicated that the mutant KITLG proteins might affect the affinity of KITLG for its receptor, c-KIT. According to the 2015 ACMG guidelines, the novel mutation c.104A>T was ‘likely pathogenic’.Conclusions: To date, most of the identified KITLG mutations have been clustered within the conserved VTNNV motif (amino acids 33-37) in exon 2. The known mutations are only involved in 33V, 34T, 36N, and 37V but not 35N. We have now identified a novel mutation in KITLG, c.104A>T, that was first reported in FPHH within the conserved 35N motif. These results strengthen our understanding of FPHH and expand the mutational spectrum of the KITLG gene.

scholarly journals Identification of a novel mutation in the KITLG gene in a Chinese family with familial progressive hyper- and hypopigmentation

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jianbo Wang ◽  
Weisheng Li ◽  
Naihui Zhou ◽  
Jingliu Liu ◽  
Shoumin Zhang ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Direct Sequencing ◽  
Three Dimensional ◽  
Chinese Family ◽  
The Novel ◽  
Exon 2 ◽  
Coding Regions ◽  
Pathogenicity Prediction ◽  
Café Au Lait Spots ◽  
Genetics And Genomics

Abstract Background Familial progressive hyper- and hypopigmentation (FPHH, MIM 145250) is a rare hereditary skin disorder that is predominantly characterized by progressive, diffuse, partly blotchy hyperpigmented lesions intermingled with scattered hypopigmented spots, lentigines and sometimes Cafe-au-lait spots (CALs). Heterozygous mutations of the KIT ligand (KITLG, MIM 184745) gene are responsible for FPHH. To date, only eight KITLG mutations have been reported to be associated with FPHH, and no clear genotype–phenotype correlations have been established. This study aimed to identify the causative mutations in the KITLG gene in two Chinese FPHH patients. Methods Direct sequencing of the coding regions of KITLG was performed. Pathogenicity prediction was performed using bioinformatics tools, including SIFT, Polyphen2, and SWISS-MODEL, and the results were further evaluated according to the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. Results The novel mutation c.104A > T (p.Asn35Ile) and the recurrent mutation c.101C > T (p.Thr34Ile) in KITLG were identified. As shown using SIFT and Polyphen-2 software, both mutations identified in this study were predicted to be detrimental variations. Three-dimensional protein structure modeling indicated that the mutant KITLG proteins might affect the affinity of KITLG for its receptor, c-KIT. According to the 2015 ACMG guidelines, the novel mutation c.104A > T was ‘likely pathogenic’. Conclusions To date, most of the identified KITLG mutations have been clustered within the conserved VTNNV motif (amino acids 33–37) in exon 2. The known mutations are only involved in 33 V, 34 T, 36 N, and 37 V but not 35 N. We have now identified a novel mutation in KITLG, c.104A > T, that was first reported in FPHH within the conserved 35 N motif. These results strengthen our understanding of FPHH and expand the mutational spectrum of the KITLG gene.

Intranuclear Crystals in Regenerating Canine Kidneys

1973 ◽  
Vol 31 ◽  
pp. 412-413
Author(s):  
D.G. Osborne ◽  
L.J. McCormack ◽  
M.O. Magnusson ◽  
W.S. Kiser
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Tubular Epithelial Cell ◽  
Tubular Epithelial Cells ◽  
Cell Nuclei ◽  
Crystalline Structures ◽  
Small Crystals ◽  
Membrane Bound

During a project in which regenerative changes were studied in autotransplanted canine kidneys, intranuclear crystals were seen in a small number of tubular epithelial cells. These crystalline structures were seen in the control specimens and also in regenerating specimens; the main differences being in size and number of them. The control specimens showed a few tubular epithelial cell nuclei almost completely occupied by large crystals that were not membrane bound. Subsequent follow-up biopsies of the same kidneys contained similar intranuclear crystals but of a much smaller size. Some of these nuclei contained several small crystals. The small crystals occurred at one week following transplantation and were seen even four weeks following transplantation. As time passed, the small crystals appeared to fuse to form larger crystals.

scholarly journals DNA Damage Response Pathway and Replication Fork Stress During Oligonucleotide Directed Gene Editing

2012 ◽  
Vol 1 ◽  
pp. e18 ◽  
Author(s):  
Melissa Bonner ◽  
Bryan Strouse ◽  
Mindy Applegate ◽  
Paula Livingston ◽  
Eric B Kmiec
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Replication Fork ◽  
Gene Editing ◽  
Damage Response ◽  
Dna Damage Response Pathway

scholarly journals Structural basis of γH2AX recognition by human PTIP BRCT5-BRCT6 domains in the DNA damage response pathway

FEBS Letters ◽  
2011 ◽  
Vol 585 (24) ◽  
pp. 3874-3879 ◽  
Author(s):  
Wei Yan ◽  
Zhenhua Shao ◽  
Fudong Li ◽  
Liwen Niu ◽  
Yunyu Shi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Structural Basis ◽  
Damage Response ◽  
Dna Damage Response Pathway

scholarly journals RTT109 AND Fun30 proteins mediate epigenetic regulation of the DNA damage response pathway in C. albicans

2021 ◽  
Author(s):  
Prashant Kumar Maurya ◽  
Pramita Garai ◽  
Kaveri Goel ◽  
Himanshu Bhatt ◽  
Aarti Goyal ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Regulation Of Gene Expression ◽  
Repair Pathway ◽  
Fungal Cell ◽  
Opportunistic Fungi ◽  
Damage Response ◽  
H3 Acetylation ◽  
Dna Damage Response Pathway

Fun30, an ATP-dependent chromatin remodeller, from S. cerevisiae mediates both regulation of gene expression as well as DNA damage response/repair. In this paper, we have characterized the biochemical and physiological function of Fun30 from the opportunistic fungi, C. albicans. Biochemically, the protein shows DNA-stimulated ATPase activity. Physiologically, the protein co-regulates transcription of RTT109, TEL1, MEC1, and SNF2-genes that encode for proteins involved in DNA damage response and repair pathway. The expression of FUN30, in turn, is regulated by histone H3 acetylation catalysed by Rtt109 encoded by RTT109. The RTT109Hz/FUN30Hz mutant strain shows sensitivity to oxidative stress and resistance to MMS as compared to the wild type strain. Quantitative PCR showed that the sensitivity to oxidative stress results from downregulation of MEC1, RAD9, MRC1 and RAD5 expression; ChIP experiments showed Fun30 but not H3ac regulates the expression of these genes in response to oxidative stress. In contrast, on treatment with MMS, the expression of RAD9 is upregulated and this upregulation is co-regulated by both Fun30 and H3 acetylation catalysed by Rtt109. Thus, Fun30 and H3 acetylation mediate the response of the fungal cell to genotoxic agents in C. albicans by regulating the expression of DNA damage response and repair pathway genes.

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