scholarly journals Alport Syndrome: De Novo Mutation in the COL4A5 Gene Converting Glycine 1205 to Valine

2012 ◽  
Vol 6 ◽  
pp. CMPed.S7509 ◽  
Author(s):  
Pilar Antón-Martín ◽  
Cristina Aparicio López ◽  
Soraya Ramiro-León ◽  
Sonia Santillán Garzón ◽  
Fernando Santos-Simarro ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Alport Syndrome ◽  
De Novo ◽  
De Novo Mutation ◽  
Molecular Defect ◽  
Detection Rates ◽  
Col4a5 Gene ◽  
Type Iv ◽  
Genes Encoding ◽  
Conclusive Diagnosis

Background Alport syndrome is a primary basement membrane disorder arising from mutations in genes encoding the type IV collagen protein family. It is a genetically heterogeneous disease with different mutations and forms of inheritance that presents with renal affection, hearing loss and eye defects. Several new mutations related to X-linked forms have been previously determined. Methods We report the case of a 12 years old male and his family diagnosed with Alport syndrome after genetic analysis was performed. Result Anew mutation determining a nucleotide change C.3614G > T (p. Gly1205Val) in hemizygosis in the COL4A5 gene was found. This molecular defect has not been previously described. Conclusion Molecular biology has helped us to comprehend the mechanisms of pathophysiology in Alport syndrome. Genetic analysis provides the only conclusive diagnosis of the disorder at the moment. Our contribution with a new mutation further supports the need of more sophisticated molecular methods to increase the mutation detection rates with lower costs and less time.

De novo mutation in the COL4A5 gene converting glycine 325 to glutamic acid in Alport syndrome

1992 ◽  
Vol 1 (2) ◽  
pp. 127-129 ◽  
Author(s):  
Alessandra Renieri ◽  
Marco Seri ◽  
Jeanne C. Myers ◽  
Taina pihlajaniemi ◽  
Laura Massella ◽  
...  
Keyword(s):  
Glutamic Acid ◽  
Alport Syndrome ◽  
De Novo ◽  
De Novo Mutation ◽  
Col4a5 Gene

scholarly journals Aminoglycoside-induced premature termination codon readthrough of COL4A5 nonsense mutations that cause Alport syndrome

2021 ◽  
Author(s):  
Kohei Omachi ◽  
Hirofumi Kai ◽  
Michel Roberge ◽  
Jeffrey H Miner
Keyword(s):  
Alport Syndrome ◽  
Premature Termination ◽  
Genetic Diseases ◽  
Premature Termination Codon ◽  
Full Length ◽  
Termination Codon ◽  
Reporter System ◽  
Nonsense Mutations ◽  
Type Iv ◽  
Genes Encoding

Alport syndrome (AS) is characterized by glomerular basement membrane (GBM) abnormalities leading to progressive glomerulosclerosis. Mutations in the COL4A3, COL4A4 or COL4A5 genes encoding type IV collagen α3α4α5 cause AS. Truncated α3, α4, and α5 chains lacking an intact COOH-terminal noncollagenous domain due to a premature termination codon (PTC) cannot assemble into heterotrimers or incorporate into the GBM. Therefore, achieving full-length protein expression is a potential therapy for AS caused by truncating nonsense mutations. Small molecule-based PTC readthrough (PTC-RT) therapy has been well studied in other genetic diseases, but whether PTC-RT is applicable to AS is unexplored. To investigate the feasibility of PTC-RT therapy in AS, we made a cDNA to express COL4A5 fused to a C-terminal NanoLuc luciferase (NLuc) to monitor full-length translation. Full-length COL4A5-NLuc produces luminescence, but mutants truncated due to a PTC do not. To screen for COL4A5 nonsense mutants susceptible to PTC-RT, we introduced 49 individual nonsense mutations found in AS patients into the COL4A5-NLuc cDNA. Luciferase assays revealed that 11 mutations (C29X, S36X, E130X, C1521X, R1563X, C1567X, W1594X, S1632X, R1683X, C1684X and K1689X) were susceptible to PTC-RT induced by G418, which is known to have high readthrough activity. Moreover, we found that some next-generation "designer" PTC-RT drugs induced RT, and RT enhancer compounds increased the efficacy of PTC-RT in a G418-susceptible PTC mutant. These results suggest that PTC-RT therapy is a feasible approach for some patients with AS. Our luciferase-based COL4A5 translation reporter system will contribute to further development of PTC-RT therapies in a personalized medicine approach to treating AS.

scholarly journals De novo X-linked Alport syndrome in a 3-year-old girl

2019 ◽  
Vol 12 (7) ◽  
pp. e230183
Author(s):  
Hiroshi Komatsu ◽  
Takeshi Goda ◽  
Kandai Nozu
Keyword(s):  
Alport Syndrome ◽  
De Novo ◽  
Adult Life ◽  
Electron Microscopic ◽  
The Family ◽  
Early Adult Life ◽  
Stage Renal Disease ◽  
End Stage ◽  
Conclusive Diagnosis ◽  
Inherited Kidney Disease

Alport syndrome (AS) is an inherited kidney disease that may lead to end-stage renal disease in early adult life. It is a clinically and genetically heterogeneous nephropathy. The possibility of a patient with haematuria or proteinuria being diagnosed as having AS cannot be excluded even if the patient is female or if the family history is unknown. We report a 3-year-old girl with a de novo frameshift mutation, c.3906delA p.(Gly1303Aspfs*17), in the COL4A5 gene. The significance of the electron microscopic study on the glomerular basement membrane must be emphasised because it is the first step towards the diagnosis of AS. Genetic analysis provides the only conclusive diagnosis of AS, by determining the mode of inheritance and prognosis.

scholarly journals An insertional frameshift mutation of the beta-spectrin gene associated with elliptocytosis in spectrin nice (beta 220/216)

Blood ◽  
1991 ◽  
Vol 78 (2) ◽  
pp. 517-523 ◽  
Author(s):  
WT Tse ◽  
PG Gallagher ◽  
B Pothier ◽  
FF Costa ◽  
A Scarpa ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Frameshift Mutation ◽  
De Novo ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
De Novo Mutation ◽  
Molecular Defect ◽  
Beta Chain ◽  
Alpha Chain ◽  
Oligonucleotide Hybridization

Abstract Spectrin Nice (beta 220/216) is a spectrin variant associated with a shortened beta chain found in a patient with elliptocytosis. The shortened beta chain (beta' chain) appeared as an additional band of approximately 216 Kd on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and was defective in its ability to be phosphorylated. There were increased amounts of spectrin dimers in crude spectrin extracts from the propositus and the association constant of spectrin dimer self-association was decreased. There was an associated increase of the alpha I 74-Kd fragment from the alpha chain after partial trypic digestion of spectrin. To identify the underlying molecular defect, we analyzed cDNA for beta spectrin obtained by polymerase chain reaction amplification of reverse-transcribed reticulocyte messenger RNA from peripheral blood of the propositus. DNA sequencing of individual as well as pooled subclones showed that two extra bases (GA) are inserted in codon no. 2046 in one allele of the beta-spectrin gene. The insertion results in a frameshift mutation and generates an aberrant C- terminus truncated by about 4 Kd, consistent with the estimated size of the beta' chain observed. By allele-specific oligonucleotide hybridization, the insertion was shown to be present in the propositus and absent in his parents, confirming a previous proposal that it is a de novo mutation. The determination of the location of the mutation in spectrin Nice points to specific regions of the beta-spectrin chain where phosphorylation may occur. A model is proposed to describe the interaction between the alpha- and beta-spectrin chains and to explain the effects of the mutation found in spectrin Nice on the trypsin digestion pattern of its associated alpha chain.

scholarly journals Identification of 17 mutations in ten exons in the COL4A5 collagen gene, but no mutations found in four exons in COL4A6: a study of 250 patients with hematuria and suspected of having Alport syndrome.

1996 ◽  
Vol 7 (5) ◽  
pp. 702-709 ◽  
Author(s):  
N Heiskari ◽  
X Zhang ◽  
J Zhou ◽  
A Leinonen ◽  
D Barker ◽  
...  
Keyword(s):  
Hot Spots ◽  
Alport Syndrome ◽  
Type Iv Collagen ◽  
Polymerase Chain Reaction Amplification ◽  
Col4a5 Gene ◽  
Type Iv ◽  
Reaction Amplification ◽  
Male Patients ◽  
Polymerase Chain ◽  
Collagen Genes

Conditions for polymerase chain-reaction amplification of ten exon regions (Exons 3, 7, 11 through 13, and 15 through 19) of the collagen COL4A5 gene and four exon regions (Exons 2, and 12 through 14) of the COL4A6 gene were sequenced and established in this study. These Type IV collagen genes contain 51 and 48 exons, respectively. The sequences of these exons were determined in the two genes in 250 male patients with hematuria and suspected Alport syndrome. Seventeen mutations were found in nine of the ten exons studied in the COL4A5 gene in 17 patients, whereas no mutations were identified in COL4A6. One mutation was identical in two patients known to be unrelated. The results indicate that mutations in COL4A5 that leading to renal failure are more frequent than those involved in classic Alport syndrome, and also that mutations in COL4A6 are not likely to cause this disease. Furthermore, mutations in COL4A5 are distributed quite randomly and no "hot spots" were found.

scholarly journals An insertional frameshift mutation of the beta-spectrin gene associated with elliptocytosis in spectrin nice (beta 220/216)

Blood ◽  
1991 ◽  
Vol 78 (2) ◽  
pp. 517-523
Author(s):  
WT Tse ◽  
PG Gallagher ◽  
B Pothier ◽  
FF Costa ◽  
A Scarpa ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Frameshift Mutation ◽  
De Novo ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
De Novo Mutation ◽  
Molecular Defect ◽  
Beta Chain ◽  
Alpha Chain ◽  
Oligonucleotide Hybridization

Spectrin Nice (beta 220/216) is a spectrin variant associated with a shortened beta chain found in a patient with elliptocytosis. The shortened beta chain (beta' chain) appeared as an additional band of approximately 216 Kd on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and was defective in its ability to be phosphorylated. There were increased amounts of spectrin dimers in crude spectrin extracts from the propositus and the association constant of spectrin dimer self-association was decreased. There was an associated increase of the alpha I 74-Kd fragment from the alpha chain after partial trypic digestion of spectrin. To identify the underlying molecular defect, we analyzed cDNA for beta spectrin obtained by polymerase chain reaction amplification of reverse-transcribed reticulocyte messenger RNA from peripheral blood of the propositus. DNA sequencing of individual as well as pooled subclones showed that two extra bases (GA) are inserted in codon no. 2046 in one allele of the beta-spectrin gene. The insertion results in a frameshift mutation and generates an aberrant C- terminus truncated by about 4 Kd, consistent with the estimated size of the beta' chain observed. By allele-specific oligonucleotide hybridization, the insertion was shown to be present in the propositus and absent in his parents, confirming a previous proposal that it is a de novo mutation. The determination of the location of the mutation in spectrin Nice points to specific regions of the beta-spectrin chain where phosphorylation may occur. A model is proposed to describe the interaction between the alpha- and beta-spectrin chains and to explain the effects of the mutation found in spectrin Nice on the trypsin digestion pattern of its associated alpha chain.

scholarly journals Structure of the Human Type IV Collagen Gene COL4A3 and Mutations in Autosomal Alport Syndrome

2001 ◽  
Vol 12 (1) ◽  
pp. 97-106
Author(s):  
LAURENCE HEIDET ◽  
CHRISTELLE ARRONDEL ◽  
LIONEL FORESTIER ◽  
LOLA COHEN-SOLAL ◽  
GERALDINE MOLLET ◽  
...  
Keyword(s):  
Alport Syndrome ◽  
Autosomal Recessive ◽  
Type Iv Collagen ◽  
Collagen Gene ◽  
Missense Mutations ◽  
Autosomal Recessive Form ◽  
Type Iv ◽  
Recessive Form ◽  
Genes Encoding ◽  
Intron Structure

Abstract. Mutations in either the COL4A3 or the COL4A4 genes, encoding the α3 and α4 chains of type IV collagen, are responsible for the autosomal-recessive form of Alport syndrome, a progressive hematuric nephropathy characterized by glomerular basement membrane abnormalities. Reported here are the complete COL4A3 exon-intron structure and a comprehensive screen for mutations of the 52 COL4A3 exons in 41 unrelated patients diagnosed as having autosomal Alport syndrome. This resulted in the identification of 21 mutations that are expected to be causative. Furthermore, it is shown that heterozygous COL4A3 missense mutations, when symptomatic, can be associated with a broad range of phenotypes, from familial benign hematuria to the complete features of Alport syndrome nephropathy.

scholarly journals Severe restless legs syndrome in a family with Alport syndrome

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Davide Sparasci ◽  
Andrea Rossinelli ◽  
Raffaele Ferri ◽  
Pietro Cippà ◽  
Andrea Rinaldi ◽  
...  
Keyword(s):  
Restless Legs Syndrome ◽  
Sleep Disturbances ◽  
Alport Syndrome ◽  
Periodic Limb Movements ◽  
Inherited Disease ◽  
Paradoxical Response ◽  
Restless Legs ◽  
Type Iv ◽  
Genes Encoding

Abstract Background Restless legs syndrome (RLS) is a common sleep-related movement disorder characterized by an urge to move the legs during inactivity, especially at evening-night. RLS is highly prevalent in patients with kidney failure and have an impact on quality of life, mood, sleep quality and overall on compliance to the dialysis. Alport syndrome (AS) is a rare inherited disease, predominantly X-linked, secondary to mutations in genes encoding α3, α4 or α5 chains of type IV collagen, and characterized by hematuria, chronic kidney disease, neurosensory deafness, and lenticonus. Case presentation Here we describe a family with a combination of X-linked AS and severe RLS accompanied by periodic limb movements during sleep (PLMS). In the first patient we identified, RLS was complicated by a paradoxical response to dopamine agonists named “augmentation”, leading to sleep disruption, hallucinations and five peritoneal perforations during the peritoneal dialysis due to the difficulty to rest still. Therapeutic adjustments and renal transplantation improved RLS and PLMS. In two brothers, severe RLS prevented a compliance with hemodialysis. Female family members carrying the mutation were also affected by RLS, while those without the mutations were RLS-free. Conclusions RLS has not been reported earlier in association with AS, but the peculiar combinations observed in this family will stimulate further clinical studies and motivate nephrologists to seek for RLS symptoms and sleep disturbances in AS patients.

Sign in / Sign up

Export Citation Format

Share Document