BACKGROUND Alport syndrome(AS)is an inherited disease of the glomerular basement membrane caused by mutations in genes encodingα3,α4,orα5 chains of type IV collagen.It manifests with hematuria or proteinuria,which ...BACKGROUND Alport syndrome(AS)is an inherited disease of the glomerular basement membrane caused by mutations in genes encodingα3,α4,orα5 chains of type IV collagen.It manifests with hematuria or proteinuria,which is often accompanied by hearing impairments and ocular abnormalities.Histopathologically,AS shows mesangial proliferation and sometimes incidental immunoglobulin A(IgA)deposition.Hematuria or proteinuria is also a common presentation in patients with IgA nephropathy that makes it difficult to differentially diagnose AS and IgA nephropathy solely based on these clinical and pathological features.CASE SUMMARY Herein,we present the case of a 59-year-old female patient who was admitted to our hospital with persistent microscopic hematuria and occasional proteinuria that had lasted for>2 years.This patient had a familial history of renal disease and was diagnosed with autosomal dominant AS(ADAS)and IgA nephropathy based on the findings of renal biopsy as well as genetic testing performed using whole-exome sequencing,which suggested that the patient carried a novel heterozygous variation(c.888G>A:p.Gln296Gln)in the COL4A3 gene that enriches the mutation spectrum of ADAS.The proband received an angiotensin receptor blocker therapy after a definitive diagnosis was established.After one year of therapy,a significant reduction in proteinuria was observed.The number of microscopic red blood cells per high-power field decreased to one-quarter of the baseline levels.Renal function also maintained well during the follow-up.CONCLUSION Our case highlights the significance of performing kidney biopsy and genetic testing in the diagnosis of AS and familial IgA nephropathy.展开更多
Background:Collagen type Ⅳ(COL4)-related nephropathy includes a variety of kidney diseases that occur with or without extra-renal manifestations caused by COL4A3-5 mutations.Previous studies revealed several novel mu...Background:Collagen type Ⅳ(COL4)-related nephropathy includes a variety of kidney diseases that occur with or without extra-renal manifestations caused by COL4A3-5 mutations.Previous studies revealed several novel mutations,including three COL4A3 missense mutations (G619R,G801R,and C1616Y) and the COL4A3 chr:228172489delA c.4317delA p.Thr1440ProfsX87 frameshift mutation that resulted in a truncated NC1 domain (hereafter named COL4A3 c.4317delA);however,the mutation mechanisms that lead to podocyte injury remain unclear.This study aimed to further explore the mutation mechanisms that lead to podocyte injury.Methods:Wild-type (WT) and four mutant COL4A3 segments were constructed into a lentiviral plasmid,then stably transfected into human podocytes.Real-time polymerase chain reaction and Western blotting were applied to detect endoplasmic reticulum stress (ERS)-and apoptosis-related mRNA and protein levels.Then,human podocytes were treated with MG132 (a proteasome inhibitor) and brefeldin A (a transport protein inhibitor).The human podocyte findings were verified by the establishment of a mus-Col4a3 knockout mouse monoclonal podocyte using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Casg) technology.Results:Our data showed that COL4A3 mRNA was significantly overexpressed in the lentivirus stably transfected podocytes.Moreover,the COL4A3 protein level was significantly increased in all groups except the COL4A3 c.4317delA group.Compared to the other test groups,the COL4A3 c.4317delA group showed excessive ERS and apoptosis.Podocytes treated with MG 132 showed remarkably increased intra-cellular expression of the COL4A3 c.4317delA mutation.MG132 intervention improved higher ERS and apoptosis levels in the COL4A3 c.4317delA group.Mouse monoclonal podocytes with COL4A3 chr:82717932insA c.4852insA p.Arg1618ThrfsX4 were successfully acquired;this NC1-truncated mutation suggested a higher level of ERS and relatively remarkable level of apoptosis compared to that of the WT group.Conclusions:We demonstrated that excessive ERS and ERS-induced apoptosis were involved in the podocyte injury caused by the NC1-truncated COL4A3 mutation.Furthermore,proteasome pathway intervention might become a potential treatment for collagen type Ⅳ-related nephropathy caused by a severely truncated COL4A3 mutation.展开更多
BACKGROUND Alport syndrome(ATS)is a rare hereditary disease caused by mutations in genes such as COL4A3,COL4A4,and COL4A5.ATS involves a spectrum of phenotypes ranging from isolated hematuria that is nonprogressive to...BACKGROUND Alport syndrome(ATS)is a rare hereditary disease caused by mutations in genes such as COL4A3,COL4A4,and COL4A5.ATS involves a spectrum of phenotypes ranging from isolated hematuria that is nonprogressive to progressive renal disease with extrarenal abnormalities.Although ATS can be combined with other diseases or syndromes,ATS combined with lupus nephritis has not been reported before.CASE SUMMARY A Chinese family with ATS was recruited for the current study.Clinical characteristics(including findings from renal biopsy)of ATS patients were collected from medical records,and potential causative genes were explored by whole-exome sequencing.A heterozygous substitution in intron 22 of COL4A3(NM_000091 c.2657-1G>A)was found in the patients,which was further confirmed by quantitative polymerase chain reaction.CONCLUSION Heterozygous substitution of a COL4A3 gene splice site was identified by wholeexome sequencing,revealing the molecular pathogenic basis of this disorder.In general,identification of pathogenic genes can help to fully understand the molecular mechanism of disease and facilitate precise treatment.展开更多
基金Supported by The Major Project of Zhejiang Administration of Traditional Chinese Medicine,No.2020ZZ008.
文摘BACKGROUND Alport syndrome(AS)is an inherited disease of the glomerular basement membrane caused by mutations in genes encodingα3,α4,orα5 chains of type IV collagen.It manifests with hematuria or proteinuria,which is often accompanied by hearing impairments and ocular abnormalities.Histopathologically,AS shows mesangial proliferation and sometimes incidental immunoglobulin A(IgA)deposition.Hematuria or proteinuria is also a common presentation in patients with IgA nephropathy that makes it difficult to differentially diagnose AS and IgA nephropathy solely based on these clinical and pathological features.CASE SUMMARY Herein,we present the case of a 59-year-old female patient who was admitted to our hospital with persistent microscopic hematuria and occasional proteinuria that had lasted for>2 years.This patient had a familial history of renal disease and was diagnosed with autosomal dominant AS(ADAS)and IgA nephropathy based on the findings of renal biopsy as well as genetic testing performed using whole-exome sequencing,which suggested that the patient carried a novel heterozygous variation(c.888G>A:p.Gln296Gln)in the COL4A3 gene that enriches the mutation spectrum of ADAS.The proband received an angiotensin receptor blocker therapy after a definitive diagnosis was established.After one year of therapy,a significant reduction in proteinuria was observed.The number of microscopic red blood cells per high-power field decreased to one-quarter of the baseline levels.Renal function also maintained well during the follow-up.CONCLUSION Our case highlights the significance of performing kidney biopsy and genetic testing in the diagnosis of AS and familial IgA nephropathy.
基金grants from the National Key Research and Development Program of China (No. 2016YFC0904100)National Natural Science Foundation of China (Nos. 81870460, 81570598, and 81370015)+3 种基金Science and Technology Innovation Action Plan of Shanghai Science and Technology Committee (No. 17441902200)Shanghai Municipal Education Commission, Gaofeng Clinical Medicine Grant (No. 20152207)Shanghai Jiao Tong University School of Medicine, MultiCenter Clinical Research Project (No. DLY201510)the Shanghai Health and Family Planning Committee Hundred Talents Program (No. 2018BR37).
文摘Background:Collagen type Ⅳ(COL4)-related nephropathy includes a variety of kidney diseases that occur with or without extra-renal manifestations caused by COL4A3-5 mutations.Previous studies revealed several novel mutations,including three COL4A3 missense mutations (G619R,G801R,and C1616Y) and the COL4A3 chr:228172489delA c.4317delA p.Thr1440ProfsX87 frameshift mutation that resulted in a truncated NC1 domain (hereafter named COL4A3 c.4317delA);however,the mutation mechanisms that lead to podocyte injury remain unclear.This study aimed to further explore the mutation mechanisms that lead to podocyte injury.Methods:Wild-type (WT) and four mutant COL4A3 segments were constructed into a lentiviral plasmid,then stably transfected into human podocytes.Real-time polymerase chain reaction and Western blotting were applied to detect endoplasmic reticulum stress (ERS)-and apoptosis-related mRNA and protein levels.Then,human podocytes were treated with MG132 (a proteasome inhibitor) and brefeldin A (a transport protein inhibitor).The human podocyte findings were verified by the establishment of a mus-Col4a3 knockout mouse monoclonal podocyte using clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Casg) technology.Results:Our data showed that COL4A3 mRNA was significantly overexpressed in the lentivirus stably transfected podocytes.Moreover,the COL4A3 protein level was significantly increased in all groups except the COL4A3 c.4317delA group.Compared to the other test groups,the COL4A3 c.4317delA group showed excessive ERS and apoptosis.Podocytes treated with MG 132 showed remarkably increased intra-cellular expression of the COL4A3 c.4317delA mutation.MG132 intervention improved higher ERS and apoptosis levels in the COL4A3 c.4317delA group.Mouse monoclonal podocytes with COL4A3 chr:82717932insA c.4852insA p.Arg1618ThrfsX4 were successfully acquired;this NC1-truncated mutation suggested a higher level of ERS and relatively remarkable level of apoptosis compared to that of the WT group.Conclusions:We demonstrated that excessive ERS and ERS-induced apoptosis were involved in the podocyte injury caused by the NC1-truncated COL4A3 mutation.Furthermore,proteasome pathway intervention might become a potential treatment for collagen type Ⅳ-related nephropathy caused by a severely truncated COL4A3 mutation.
基金This workwas supported by grants from the National Basic Research Program of China 973, grant no. 2012CB517600 （no. 2012CB517604）, the National Natural Science Foundation of China （no. 81030015, 81070568, 81370015, and 81000295）, the International Cooperation and Exchange Projects of Shanghai Science and Technology Committee （no. 14430721000）, and the Chinese Medical Association Clinical Research Special Fund （no. 13030280413）.
基金Supported by the Science and Technology Bureau of Jiulongpo District in Chongqing,No.2019-02-027-D.
文摘BACKGROUND Alport syndrome(ATS)is a rare hereditary disease caused by mutations in genes such as COL4A3,COL4A4,and COL4A5.ATS involves a spectrum of phenotypes ranging from isolated hematuria that is nonprogressive to progressive renal disease with extrarenal abnormalities.Although ATS can be combined with other diseases or syndromes,ATS combined with lupus nephritis has not been reported before.CASE SUMMARY A Chinese family with ATS was recruited for the current study.Clinical characteristics(including findings from renal biopsy)of ATS patients were collected from medical records,and potential causative genes were explored by whole-exome sequencing.A heterozygous substitution in intron 22 of COL4A3(NM_000091 c.2657-1G>A)was found in the patients,which was further confirmed by quantitative polymerase chain reaction.CONCLUSION Heterozygous substitution of a COL4A3 gene splice site was identified by wholeexome sequencing,revealing the molecular pathogenic basis of this disorder.In general,identification of pathogenic genes can help to fully understand the molecular mechanism of disease and facilitate precise treatment.
