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1.
Chinese Journal of Nephrology ; (12): 872-880, 2021.
Article in Chinese | WPRIM | ID: wpr-911907

ABSTRACT

Objective:To analyze the splicing mutation site of COL4A5 gene in a family with X-linked dominant Alport syndrome and explore the possibility of exon specific U1 small nuclear RNA (snRNA) gene therapy. Methods:The clinical data of the proband and family members of Alport syndrome were collected, and the gene mutations in the whole exon of a series of nephropathy genes in the proband were detected by high-throughput sequencing. The splice site changes and pathogenicity caused by COL4A5 c.546+5G>A mutation were analyzed by online software. Minigene experiment was used to verify and analyze the effect of COL4A5 gene mutation site c.546+5G>A in the proband of Alport syndrome family, and transient transfection and introduction of modified U1 snRNA to correct splicing mutation. Results:The results of gene sequencing showed that there was a hemizygous variation of COL4A5 gene in the proband and his half brother, and the variation site was c.546+5G>A. The results of online software for analyzing the pathogenicity of splice variation showed that the original donor splicing site could not be detected after mutation, suggesting that there was a great possibility of affecting splicing. The abnormal splicing mode of COL4A5 gene with c.546+5G>A mutation—deletion of exon 9 was verified by hybridized small gene detection. The abnormal splicing mutation could be partially corrected by the modified U1 snRNA. The correction ratios of ExSpeU1 (MT), ExSpeU1(E9+1), ExSpeU1(E9+9) and ExSpeU1(E9+11) to exon 9 deletion caused by c.546+5G>A were 0, 43.81%, 52.09% and 48.12%, respectively. Conclusions:The pathogenicity of the new splicing mutation of COL4A5 is verified, and the modified U1 snRNA can partially correct the abnormal splicing.

2.
Chinese Journal of Nephrology ; (12): 865-871, 2021.
Article in Chinese | WPRIM | ID: wpr-911906

ABSTRACT

Objective:To report four male COL4A5 mutation mosaicism patients with X-linked Alport syndrome, and to provide evidence for diagnosis, genetic counseling, and reproduction in the respective families and improve our knowledge of mosaicism in Alport syndrome. Methods:Suspected male mosaic patients for COL4A5 who met the following criteria: clinical diagnosis of Alport syndrome, harbored COL4A5 mutations detected using next generation sequencing or Sanger sequencing, heterozygosity for the mutant and normal COL4A5 alleles in the DNA demonstrated by Sanger sequencing, registered in the on-line registry of hereditary kidney diseases, and admitted to Peking University First Hospital during the period of April 2018 to April 2019 were enrolled. Clinical data and karyotypes were retrospectively analyzed. Genetic DNA isolated from multiple tissues was analyzed for COL4A5 gene mutations by using PCR and Sanger sequencing. Related literatures published in PubMed, CNKI and Wanfang databases were reviewed. Results:Four COL4A5 somatic and germline mosaic male patients with Alport syndrome were included in the study. Patient 1 was characterized by hematuria and proteinuria. His karyotype of peripheral blood was normal. COL4A5 c.3455-1G>A mosaicism was detected in multiple tissues (peripheral blood, saliva and urine). Patient 2 presented with hematuria and microalbuminuria. His karyotype of peripheral blood was normal. COL4A5 c.4994+1G>A mosaicism was detected in multiple tissues (peripheral blood, saliva and skin fibroblasts). Patients 3 showed hematuria without proteinuria. COL4A5 c.3535G>A mosaicism was found in genomic DNA of peripheral blood and hair. Laboratory and physical examinations of patient 4 showed hematuria and normal renal function, without proteinuria, megasoma or small testes. COL4A5 c.3106G>A mosaicism was detected in genomic DNA of skin fibroblasts. Although without karyotype analysis due to unavailable specimens, 47,XXY or 46,XY/47,XXY mosaicism was not considered according to the reproductive history and lack of clinical manifestations of megasoma and small testes in patients 3 and 4. Renal disease in 8 published male cases with mosaicism for COL4A5 was affected by mutant allelic fractions and genotype. Conclusions:Compared with hemizygous males with X-linked Alport syndrome, the renal phenotype of mosaic males was milder, and associated with mutant allelic fractions and mutation type.

3.
Article in Chinese | WPRIM | ID: wpr-908037

ABSTRACT

The clinical characteristics, mutation analysis results, and family tree of a patient with autosomal dominant Alport syndrome (ADAS), who had nephrotic syndrome as the first manifestation were examined.The proband was a 11-month-old girl who presented with nephrotic syndromes and gross hematuria.During the treatment course, the patient had steroid resistance and a poor response to Cyclosporine and Cyclophosphamide pulse therapy.Renal biopsy was performed 2 years after disease onset.Under the light microscopy, glomerular segmental mesangio-proliferative lesions were observed.The staining of type Ⅳ collagen showed the loss of the α3 chain in the glomerular basement membrane (GBM) and tubular basement membrane, and α5 chain loss in GBM.Electron microscopy showed uneven thickness of GBM, with obviously delaminated and tearing dense basement membrane (BM) layer, showing a typical lace-like change.The segmental BM was loosened and widened.Her father did not develop microscopic hematuria until 10 years later, while her grandmother had asymptomatic hematuria and proteinuria when the proband was diagnosed.A new mutation in the COL4A4 gene was found in the proband, namely c. 1715delG (p.G572Vfs * 81). Her father and grandmother carried the same mutation, but her mother and sister did not have.The clinical manifestation of ADAS is clinically heterogeneous and its incidence may be higher than what we have expected.

4.
Article in English | WPRIM | ID: wpr-760199

ABSTRACT

Alport syndrome (ATS) is an inherited glomerular disease caused by mutations in one of the type IV collagen novel chains (α3, α4, and α5). ATS is characterized by persistent microscopic hematuria that starts during infancy, eventually leading to either progressive nephritis or end-stage renal disease. There are 3 known genetic forms of ATS, namely X-linked ATS, autosomal recessive ATS, and autosomal dominant ATS. About 80% of patients with ATS have X-linked ATS, which is caused by mutations in the type IV collagen α5 chain gene, COL4A5. Although an 80% mutation detection rate is observed in men with X-linked ATS, some difficulties do exist in the genetic diagnosis of ATS. Most mutations are point mutations without hotspots in the COL4A3, COL4A4, and COL4A5 genes. Further, there are insufficient data on the detection of COL4A3 and COL4A4 mutations for their comparison between patients with autosomal recessive or dominant ATS. Therefore, diagnosis of ATS in female patients with no apparent family history can be challenging. Therefore, in this study, we used whole-exome sequencing (WES) to identify mutations in type IV collagen in 2 girls with glomerular basement membrane structural changes suspected to be associated with ATS; these patients had no relevant family history. Our results revealed de novo c.4688G>A (p.Arg1563Gln) and c.2714G>A (p.Gly905Asp) mutations in COL4A5. Therefore, we suggest that WES is an effective approach to obtain genetic information in ATS, particularly in female patients without a relevant family history, to detect unexpected DNA variations.


Subject(s)
Child , Collagen Type IV , Diagnosis , DNA , Exome , Female , Glomerular Basement Membrane , Hematuria , Humans , Kidney Failure, Chronic , Korea , Male , Nephritis , Nephritis, Hereditary , Point Mutation
5.
International Eye Science ; (12): 409-413, 2019.
Article in Chinese | WPRIM | ID: wpr-719740

ABSTRACT

@#Alport syndrome(AS)is a genetic disease characterized by abnormal basement membrane structure of the kidneys, ears and eyes. The incidence of the disease is 1:5000 approximately. The report on ocular manifestations is relatively scarce, however, it is of great value to diagnosis of the disease. The ocular tissue histopathological analysis provides an effective method to uncover the pathological mechanisms of AS. Besides, it is good for understanding and treatment of AS.

6.
Article in Chinese | WPRIM | ID: wpr-797494

ABSTRACT

Objective@#To explore the genetic basis of a child with chronic kidney disease featuring renal shrinkage and creatinine increase.@*Methods@#Peripheral venous blood samples were taken from the child, his brother and two parents and subjected to whole exome sequencing. Suspected mutations were verified by Sanger sequencing. Bioinformatic analysis was carried out to predict the influence of mutations on the structure and function of the protein product.@*Results@#High-throughput and Sanger sequencing revealed that the child has carried compound heterozygous mutations of the COL4A4 gene, namely c. 4550T>G in exon 47 (inherited from his mother) and c. 199C>T in exon 5 (inherited from his father). Neither mutation was reported previously. Bioinformatic analysis showed that both mutations have located in highly conserved regions. The same mutations were not found in his brother.@*Conclusion@#The compound heterozygous c. 4550T>G and c. 199C>T mutations probably underlie the disease in this child. The findings have enriched the mutation spectrum of the COL4A4 gene.

7.
Journal of Medical Postgraduates ; (12): 619-623, 2019.
Article in Chinese | WPRIM | ID: wpr-818291

ABSTRACT

Objective The purpose of this study was to identify a pathogenic variant in a Chinese family with Alport syndrome and analyze the pathogenicity of the variant. Methods Using targeted region capture and high-throughput sequencing technology, we identified the genetic variant of the proband with Alport syndrome, verified the variant in the family members by Sanger sequencing, and analyzed its influence on the pre-mRNA splicing process by in vitro minigene assay. Results A heterozygous variant c.2767G>T (p.Gly923Cys) was identified as a novel variant in exon 32 of the COL4A5 gene in the proband, which was confirmed by Sanger sequencing to be cosegregated with disease in the family. The minigene assay demonstrated that the c.2767G>T variant induced deletion of exon 32 of the COL4A5 gene. Conclusion A novel COL4A5 mutation was identified by targeted region capture and high-throughput sequencing, which has enriched the gene mutation spectrum of Alport syndrome. The exonic mutation c.2767G>T confirmed to be a splicing mutation by in vitro minigene assay, which may lead to a deeper insight into the molecular pathogenesis of Alport syndrome.

8.
Article in Chinese | WPRIM | ID: wpr-696584

ABSTRACT

Objective To investigate the clinical efficacy and safety of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) in treatment of children with Alport syndrome (AS).Methods A total of 22 children with AS in Department of Pediatrics,Guangzhou First People's Hospital and Department of Pediatrics,Shenzhen People's Hospital between January 2013 and December 2017 were selected.But four children were not included in this study since they did not take medication regularly,and the other 18 cases were included in this study.All the 18 children were initially treated with ACEI.The observation time was from 1 to 5 years.If the symptoms were not effectively controlled,treatment plan would be changed to ACEI combined with ARB treatment.The observation time was from 1 to 3 years.The clinical data and laboratory examination results [including 24-hour urine protein (mg/24 h),urine red blood cell count,plasma albumin (Alb),urea nitrogen (BUN),serum creatinine (Scr),total cholesterol (TC)] were collected for retrospective analysis.Results Eighteen patients started their treatment with ACEI inhibitors (Fosinopril).Within 2 years of treatment,the urinary protein and urinary red blood cells in the children decreased to 47.7% and 41.3%,respectively,and the differences were all statistically significant (all P < 0.05),and the renal function was stable within the normal range.Two years later,7 patients had elevation of urinary protein and urinary erythrocyte elevations and decrease of renal function,and they were treated with ACEI and ARB (Losartan).The other children had no significant change in urine protein and urine red blood cells in the 3 rd,4th,and 5th year,and their renal function was stable.After ACEI treatment alone for 5 years,urinary protein was 47.8% lower than before treatment,and the difference was statistically significant (P < 0.05);urinary red blood cells decreased to 32.0% compared with before treatment,and the difference was statistically significant (P < 0.05).Seven patients with ACEI alone had poor efficacy,after the treatment with ACEI combined with ARB,the urinary protein and urine red blood cells were lower in the first year and the renal function improved.There was no significant change in urinary protein and urine red blood cells in the 2nd and 3rd year,and renal function was stable.After ACEI combined with ARB treatment for 3 years,urinary protein decreased to 42.3% before treatment,and the difference was statistically significant (P < 0.05),and urinary red blood cells decreased to 46.9% compared with before treatment,and the difference was statistically significant(P < 0.05).Conclusions ACEI treatment of children with AS can reduce urine protein and help delay renal failure.For children with poor efficacy of ACEI treatment,ACEI combined with ARB may have a certain effect.ARB can be used as an adjunctive treatment for patients with AS who have a poor response to ACEI alone.

9.
Article in Chinese | WPRIM | ID: wpr-692427

ABSTRACT

Alport syndrome is a rare genetic disorder of specialized basement membranes in the kidney,ear,and eye.Eighty percent of patients have X-linked disease caused by mutations in the COL4A5 gene;autosomal forms of the other Alport syndrome are caused by mutations in COI4A3 and COL4A4 genes.These mutations result in progressive irregular thickening,thinning,and splitting of the GBM,leading to end stage renal failure.During the past two decades,research into this rare disease has focused on the effects of mutations in collagen type Ⅳ α chains and the role of changes in podocytes and the glomerular basement membrane that lead to early kidney fibrosis.In this review,we discuss the latest basic and clinical research on Alport syndrome,focusing on the roles of podocyte pathology and the extracellular matrix.

10.
Article in English | WPRIM | ID: wpr-136751

ABSTRACT

PURPOSE: Thin glomerular basement membrane nephropathy (TBMN) is, along with the IgA nephropathy, the most common cause of asymptomatic hematuria in Korean children. TBMN is usually a benign renal disease not requiring treatment and is associated with a good prognosis, but some cases hematuria is indicative of a state of progressive renal insufficiency. We aimed to retrospectively evaluate clinical manifestations and renal prognosis of patients with TBMN. METHODS: Among the 428 renal biopsies performed on children at Yeungnam University Hospital between January 2000 and February 2017, 167 patients were diagnosed as having TBMN. We retrospectively investigated 167 pediatric patients and identified 59 children with follow-up duration >3 years. RESULTS: Among 59 patients, there were 33 boys and 26 girls. Mean age of onset of hematuria was 7.18±2.64 years, and mean time from onset of disease until a renal biopsy was performed was 2.48±2.10 years. There were no clinical features or laboratory findings among studied children to indicate decreased renal function during follow-up; however, one case progressed to chronic kidney disease (CKD) due to an unknown cause. There were seven patients among these related a positive family history of hematuria or renal insufficiency. CONCLUSION: Although almost all patients had normal renal functions during follow-up, there were one patient who progressed to CKD and seven patients with family history of hematuria or renal insufficiency. Moreover, four among the 428 patients over 17 years underwent repeat renal biopsies, which showed results different from their earlier biopsies.Thus, large-scales studies may be required to determine long-term prognosis of TBMN in children, and further evaluation for Alport syndrome in TBMN cases is essential.


Subject(s)
Age of Onset , Biopsy , Child , Female , Follow-Up Studies , Glomerular Basement Membrane , Glomerulonephritis, IGA , Hematuria , Humans , Nephritis, Hereditary , Prognosis , Renal Insufficiency , Renal Insufficiency, Chronic , Retrospective Studies
11.
Article in English | WPRIM | ID: wpr-136746

ABSTRACT

PURPOSE: Thin glomerular basement membrane nephropathy (TBMN) is, along with the IgA nephropathy, the most common cause of asymptomatic hematuria in Korean children. TBMN is usually a benign renal disease not requiring treatment and is associated with a good prognosis, but some cases hematuria is indicative of a state of progressive renal insufficiency. We aimed to retrospectively evaluate clinical manifestations and renal prognosis of patients with TBMN. METHODS: Among the 428 renal biopsies performed on children at Yeungnam University Hospital between January 2000 and February 2017, 167 patients were diagnosed as having TBMN. We retrospectively investigated 167 pediatric patients and identified 59 children with follow-up duration >3 years. RESULTS: Among 59 patients, there were 33 boys and 26 girls. Mean age of onset of hematuria was 7.18±2.64 years, and mean time from onset of disease until a renal biopsy was performed was 2.48±2.10 years. There were no clinical features or laboratory findings among studied children to indicate decreased renal function during follow-up; however, one case progressed to chronic kidney disease (CKD) due to an unknown cause. There were seven patients among these related a positive family history of hematuria or renal insufficiency. CONCLUSION: Although almost all patients had normal renal functions during follow-up, there were one patient who progressed to CKD and seven patients with family history of hematuria or renal insufficiency. Moreover, four among the 428 patients over 17 years underwent repeat renal biopsies, which showed results different from their earlier biopsies.Thus, large-scales studies may be required to determine long-term prognosis of TBMN in children, and further evaluation for Alport syndrome in TBMN cases is essential.


Subject(s)
Age of Onset , Biopsy , Child , Female , Follow-Up Studies , Glomerular Basement Membrane , Glomerulonephritis, IGA , Hematuria , Humans , Nephritis, Hereditary , Prognosis , Renal Insufficiency , Renal Insufficiency, Chronic , Retrospective Studies
12.
Article in Chinese | WPRIM | ID: wpr-668910

ABSTRACT

Objective:To evaluate the ability of multiplex competitive fluorescence polymerase chain reaction in detection of large deletion and duplication genotypes of X-linked Alport syndrome.Methods:Clinical diagnosis of X-linked Alport syndrome was based on either abnormal staining of type Ⅳ collagen α5 chain in the epidermal basement membrane alone or with abnormal staining of type Ⅳ collagen α5 chain in the glomerular basement membrane and Bowman's capsule/ultrastructural changes in the glomerular basement membrane typical of Alport syndrome.A total of 20 unrelated Chinese patients (13 males and 7 females) clinically diagnosed as X-linked Alport syndrome were included in the study.Their genotypes were unknown.Control subjects included a male patient with other renal disease and two patients who had large deletions in COL4A5 gene detected by multiplex ligation-dependent probe amplification.Genomic DNA was isolated from peripheral blood leukocytes in all the participants.Multiplex competitive fluorescence polymerase chain reaction was used to coamplify 53 exons of COL4A5 gene and four reference genes in a single reaction.When a deletion removed exon 1 of COL4A5 gene was identified,the same method was used to coamplify the first 4 exons of COL4A5 and COL4A6 genes,a promoter shared by COL4A5 and COL4A6 genes,and three reference genes in a single reaction.Any copy number loss suggested by this method was verified by electrophoresis of corresponding polymerase chain reaction amplified products or DNA sequencing to exclude possible DNA variations in the primer regions.Results:Genotypes of two positive controls identified by multiplex competitive fluorescence polymerase chain reaction were consistent with those detected by multiplex ligation-dependent probe amplification.Deletions were identified in 6 of the 20 patients,including two large deletions removing the 5'part of both COL4A5 and COL4A6 genes with the breakpoint located in the second intron of COL4A6,two large deletions removing more than 30 exons of COL4A5 gene,one large deletion removing at least 1 exon of COL4A5 gene,and one small deletion involving 13 bps.No duplication was found.Conclusion:Our results show that multiplex competitive fluorescence polymerase chain reaction is a good alternative to classical techniques for large deletion genotyping in X-linked Alport syndrome.

13.
Article in English | WPRIM | ID: wpr-48167

ABSTRACT

Every cell of an organism is separated and protected by a cell membrane. It is proposed that harmony between intercellular communication and the health of an organism is controlled by a system, designated the protein-homeostasis-system (PHS). Kidneys consist of a variety of types of renal cells, each with its own characteristic cell-receptor interactions and producing characteristic proteins. A functional union of these renal cells can be determined by various renal function tests, and harmonious intercellular communication is essential for the healthy state of the host. Injury to a kind of renal cells can impair renal function and induce an imbalance in total body health. Every acute or chronic renal disease has unknown etiologic substances that are responsible for renal cell injury at the molecular level. The immune/repair system of the host should control the etiologic substances acting against renal cells; if this system fails, the disease progresses to end stage renal disease. Each renal disease has its characteristic pathologic lesions where immune cells and immune proteins, such as immunoglobulins and complements, are infiltrated. These immune cells and immune proteins may control the etiologic substances involved in renal pathologic lesions. Also, genetic renal diseases and cancers may originate from a protein deficiency or malfunctioning protein under the PHS. A unified pathogenesis for renal diseases, including acute glomerulonephritis, idiopathic nephrotic syndrome, immunoglobulin A nephropathy, genetic renal diseases such as Alport syndrome, and malignancies such as Wilms tumor and renal cell carcinoma, is proposed using the PHS hypothesis.


Subject(s)
Carcinoma, Renal Cell , Cell Membrane , Complement System Proteins , Glomerulonephritis , Glomerulonephritis, IGA , Hydrogen-Ion Concentration , Immunoglobulins , Kidney Diseases , Kidney Failure, Chronic , Kidney , Nephritis, Hereditary , Nephrotic Syndrome , Protein Deficiency , Renal Insufficiency, Chronic , Wilms Tumor
14.
Article in Chinese | WPRIM | ID: wpr-510817

ABSTRACT

Objective To explore the diagnosis and differential diagnosis of IgA nephropathy.Methods The clinical data of 2 children with IgA nephropathy were retrospectively analyzed.The pertinent literatures were reviewed.Results In 2 males aged 6 and 7 years,the clinical features were a large amount of proteinuria (mainly albumin),low serum albumin,high cholesterol,and persistent microscopic hematuria,which were in line with the diagnosis of nephrotic syndrome.The effects of hormone and immunosuppressive therapy were poor.Renal pathology immunofluorescence and light microscopy findings were in accord with mild to moderate mesangial proliferative IgA nephropathy (M1E0S0T0).Electron microscope showed glomerular basement membrane lesions (layering,breakage,and uneven thickness),which could not exclude Alport syndrome.Further gene detection confirmed a pathogenic mutation of COL4A5.Conclusions It is rare that IgA nephropathy is combined IgA nephropathy at the same time.Attention should by paid to those who had a poor effect of treatment or had a related family history in IgA patients because it is possible that IgA nephropathy and IgA nephropathy may occurred at the same time.

15.
Indian J Ophthalmol ; 2016 Nov; 64(11): 847-849
Article in English | IMSEAR | ID: sea-183145

ABSTRACT

We report the first case of toric multifocal intraocular lens (IOL) implantation in both the eyes of a young patient of Alport syndrome with anterior and posterior lenticonus with a successful outcome. An 18‑year‑old female patient presented with progressively blurred vision in both eyes since 4–5 years not improving with glasses. Refraction showed high myopia with astigmatism; however, the vision did not improve beyond 6/60 with glasses correction. Clinical examination on slit lamp showed anterior and posterior lenticonus bilaterally with a classical oil droplet appearance. We performed clear lens extraction by phacoemulsification with toric multifocal IOL implantation in both eyes. Postoperatively, the patient achieved an excellent refractive outcome with the unaided vision of 6/9, N6 in both eyes.

16.
Article in English | WPRIM | ID: wpr-148721

ABSTRACT

The coexistence of Wilson disease with Alport syndrome has not previously been reported. The diagnosis of Wilson disease and its ongoing monitoring is challenging when associated with an underlying renal disease such as Alport syndrome. Proteinuria can lead to low ceruloplasmin since it is among serum proteins inappropriately filtered by the damaged glomerulus, and can also lead to increased urinary loss of heavy metals such as zinc and copper. Elevated transaminases may be attributed to dyslipidemia or drug induced hepatotoxicity. The accurate diagnosis of Wilson disease is essential for targeted therapy and improved prognosis. We describe a patient with a diagnosis of Alport syndrome who has had chronic elevation of transaminases eventually diagnosed with Wilson disease based on liver histology and genetics.


Subject(s)
Blood Proteins , Ceruloplasmin , Copper , Diagnosis , Dyslipidemias , Genetics , Hepatolenticular Degeneration , Humans , Liver , Metals, Heavy , Nephritis, Hereditary , Prognosis , Proteinuria , Transaminases , Zinc
17.
Article in Chinese | WPRIM | ID: wpr-502120

ABSTRACT

Objective To study the feasibility of testing three disease-causing genes for Alport syndrome,COL4A3,COL4A4 and COL4AS,in diagnosing patients with sporadic Alport syndrome by using targeted capture and next generation sequencing.Methods The clinical data of a 9-year-old boy suspected with Alport syndrome were collected.Genomic DNA was extracted using standard procedures from the peripheral blood leukocytes of the patient and his parents,respectively.Targeted capture and next generation sequencing and Sanger sequencing were applied to analyze the mutations in the 3 disease-causing genes.Clinical data of cases reported already with autosomal recessive Alport syndrome caused by the mutations in the COL4A4 gene were summarized.Results The patient was presented with neither family history of hematuria nor chronic renal failure.Haematuria and proteinuria were found at the age of 1 year.The patient presented with episodes of macrohaematuria and gradually developed nephrotic-level proteinuria.At the age of 8 years 7 months,bilateral sensorineural hearing loss was diagnosed.So a probable diagnosis of Alport syndrome was postulated.A compound heterozygous pathogenic mutations of 3578-1G > A and 3967 C > T(Q1323X) were identified in the COL4A4 gene in the patient.The mutation of 3578-1G > A was inherited from his father,and the mutation of Q1323X from his mother.The patient was decisively diagnosed with autosomal recessive Alport syndrome.Conclusions The test of COL4A3,COL4A4 and COL4A5 genes can help diagnose patients with sporadic Alport syndrome by using targeted capture and next generation sequencing.

18.
Article in Chinese | WPRIM | ID: wpr-502119

ABSTRACT

Objective In this study,the phenotype heterogeneity of 2 male patients with X-linked Alport syndrome from one family was analyzed and the likely reasons were discussed by reviewing the literature.Methods The clinical data at the time of diagnosis and during 5 years follow-up of 2-male patients with X-linked Alport syndrome from one family were collected.The α5 (Ⅳ) chain expression in the epidermal basement membrane was detected by indirect immunofluorescence method.COL4A5 gene mutations in skin fibroblasts and genomic DNA were detected by using reverse transcription polymerase chain reaction and direct sequencing and PCR sequencing methods from skin fibroblasts and genomic DNA,respectively.Results The diagnostic age of patient Ⅲ 1 was 14 years old.He had only microscopic hematuria,and proteinuria was negative.A negative α5 (Ⅳ) chain staining pattern was detected in his epidermal basement membrane.After 5 years follow-up without drug treatment,he was 19 years old,had persistent microscopic hematuria and normal renal function.The urinary microalbumin was 19.2-31.8 mg/L.The diagnosis age of patient Ⅱ 4 was 29 years old.The hematuria and proteinuria were found at 22 years old.He was treated with tripterygium wilfordii for 1 year.His disease progressed to an end stage of renal disease and he received hemodialysis therapy at 24 years old.He had the renal transplantation surgery at 29 years old,just 2 months before he came to hospital.And his renal function was restored.After 5 years follow-up,his urine examination and renal function were normal.Both patients had a missense mutation c.3650G > A(p.G1217D) in exon 41 in COL4A5 gene.Conclusions The different phenotypes of 2 male patients from one family with X-linked Alport syndrome were reported.The most possible reason for this is somatic mosaic variants in COL4A5 gene based on literature review.Physicians should be alert to phenotype heterogeneity in male X-linked Alport syndrome despite having the same gene mutation.

19.
Journal of Medical Postgraduates ; (12): 508-513, 2016.
Article in Chinese | WPRIM | ID: wpr-492545

ABSTRACT

Objective The article was to analyze the features of gene mutation and clinical phenotype in Alport syndrome. Methods Next-generation sequencing was applied to capture the exons of COL4A3, COL4A4, COL4A5 genes in 30 cases of children with suspected or confirmed diagnosis of Alport syndrome and Sanger method was used to identify gene mutations of related family mem-bers.Provean database was applied in protein function prediction.We collected and analyzed clinical data of AS patients on the basis of gene mutation. Results All 30 children were diagnosed with AS by gene sequencing, among whom 4 boys were autosomal reces-sive inheritance, 16 boys and 10 girls were X-linked Alport syndrome.Next-generation sequencing detected 35 different gene mutations of COL4A3, COL4A4, COL4A5, including 19 missense mutations, 2 synonymous mutations, 4 splice-site mutations, 3 truncating mu-tations, 2 insertion mutations, 4 deletion mutations and 1 compound mutations.It was observed by Sanger sequencing that 20 mutations were inherited from the mother, 8 from the father, homozygous mutation in 1 propositus from the parents respectively, 8 novel mutations and 1 with unidentified source.All the 30 children had an onset of hematuria or proteinuria, 17 cases had a positive family history, 1 case had hearing loss, and no pathogenesis or renal insufficiency was found in the children.Renal biopsy was performed on 23 children, 13 minimal change disease ( MCD) and 10 mesangial proliferative glo-merulonephritis ( MsPNG) by light microscope.Extensive lamination and split of glomerular basement membrane dense layers were found in 9 children by electron microscope. Conclusion XLAS ac-counts for most AS patients and missense mutation is the main type in pathogenic mutations.Altogether, 31 mutations without disease notification were found.Most of children showed MCD in renal biopsy, with atypical electron microscope manifestations and rare extra renal manifestations.

20.
Rev. Fac. Med. (Bogotá) ; 63(1): 143-149, ene.-mar. 2015. ilus, tab
Article in Spanish | LILACS-Express | LILACS | ID: biblio-956735

ABSTRACT

Se presenta el caso de una paciente de 4 años de edad, con hermano gemelo dicigoto asintomático, hija de padres no consanguíneos y sin antecedentes familiares de enfermedad renal. Inicia su cuadro clínico con edemas y proteinuria severa como manifestación de un síndrome nefrótico primario de cambios mínimos; este se diagnosticó por biopsia renal y, en un principio, se manejó con esteroides. Su evolución no fue adecuada debido a múltiples recaídas que la clasificaron como síndrome nefrótico corticorresistente. Por ello, se requirió un cambio en su tratamiento y una segunda biopsia renal, cuyo resultado histológico sorprendió al grupo médico tratante porque los cambios en la membrana basal glomerular confirmaban que se trataba de un Síndrome de Alport.


We present the case of a 4 year-old girl patient, with an asymptomatic dizygotic twin brother, child of non-consanguineous parents and with no family history of renal disease. Her clinical picture started with edema and severe proteinuria as manifestations of a minimal change nephrotic syndrome that was diagnosed by renal biopsy and initially treated with steroids. Her clinical course was complicated by multiple relapses that classified her as a patient presenting a steroid-resistant nephrotic syndrome, her treatment was changed and a second renal biopsy was needed. Histology outcome of biopsy surprised the treating medical group because changes in glomerular basal membrane revealed that it was in fact an Alport syndrome.

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