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Objective To elucidate the clinicopathological and hereditary characteristics in Fabry nephropathy.Methods The clinical and pathological features of 14 patients with Fabry nephropathy were collected.The activities of α-Gal A were measured in 4 probands.Screenings of GLA mutations were done in 12 patients.Results The ratio of Fabry nephropathy in the patients with renal biopsy was 0.074 ％ (14/19 005),the average diagnostic age was (30.57±9.32) years,male to female ratio was 2.5∶ 1.All the patients had proteinuria,and the median of urine total protein (UTP)was 1.71 g/24 h (0.32-4.71 g/24 h).Two of them got nephrotic proteinuria,5 of them got microscopic hematuria,4 of them got renal function insufficiency.Angiokeratomas was the most common manifestation (10/14),followed by cardiac involvement (6/14).Hypohidrosis and diseases of central neural system could also be seen in these patients.There were 9 classic phenotype,the remaining 5 were variants/renal variants.The family information was collected in 10 pedigrees,6 of them had family histories of kidney disease.Renal pathology showed vacuolization of glomerular visceral epithelial cells was the prominent feature,global and segmental glomerulosclerosis were seen in some patients by light microscopy.The myelin bodies or zebra bodies were identified in podocytes by electron microscopy,but only were found in some podocytes of 2 females.The activity of α-Gal A was decreased compared with the normal range in 4 probands.The mutations of GLA were demonstrated in 11 patients.Three novel mutations of GLA gene were identified,which were all deletion/insertion mutations with classic phenotypes.Most variants carried the mutations located in the buried/partial buried areas of α-Gal A (3/11).The classical phenotype carried GLA mutations as W162X,F169S,S201F,N272K,L310R,while variant phenotype carried GLA mutations as I91T,R112H,Q312H.Conclusions The ratio of Fabry nephropathy in patients with renal biopsy is 0.074％.Angiokeratomas and cardiac involvement are often accompanied with Fabry nephropathy.The genotypes of GLA may have close relationships with the phenotypes of Fabry nephopathy.
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Objective To elucidate the features of clinicopathology and mutation in Fabry disease complicated with thin basement membrane nephropathy (TBMN), and to investigate the kindred. Methods Data of clinicopathology and gene mutation of a female patient of Fabry disease complicated with TBMN admitted to the Department of Nephro]ogy in our hospital were analyzed. Members of her kindred were investigated simultaneously. Results Proband was a 41-year-old Chinese woman who presented syndrome of Fabry disease and TBMN including angiokeratomas, chronic pain, tinnitus, vertigo, left ventricular hypertrophy and nephropathy as proteinuria, microscopic hematuria and hypertension. A percutaneous renal biopsy was performed on the proband, which was consistent with FSGS and vaculization of podocytes by light microscopy.Electron microscopy showed concentric lamellated inclusions in some podocytes. Diffuse thinning of glomerular basement membrane (GBM) with a mean thickness of (216±31) nm was found. The diagnosis of TBMN with suspected Fabry disease was identified. Family screening showed that her daughter had microscopic hematuria, tinnitus and neuropathic pain. One of her sisters only had microscopic hematuria. The activity of α-galacsidase A (α-Gal A )enzyme in the proband and her daughter was 33 units and 75 units respectively (the normal range is 100 to 500 units). They all carried the novel GLA mutation 1208 ins 21 bp and COL4A3 SNP c: 3627G＞A(p:M1209I). While her sister who only had microscopic hematuria just carried the variant of COL4A3 gene-c:3627G ＞A (p:M1209I), and had the normal activity of α-Gal A with no mutation of GLA.Conclusion TBMN should be considered in the patients of Fabry disease with the condition of benign familial hematuria.
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Objective To detect the proteins structure encoded by COL4A4 gene with different missense mutations of thin basement membrane nephropathy (TBMN) and to analyze the effect of gene mutation on the secondary structure of α4 (Ⅳ) chain and its association with phenotype. Methods A COL4A4-linked TBMN patient with FSGS by a missense mutation (g. 1214G>A resulting in p. G405E) diagnosed by clinical manifestations, family history and renal biopsy examination, as well as two controls (one healthy, one pure TBMN carrying a g. 1550G>A mutation resulting in p. G448S) were enrolled in this study. The fragments of cDNA with the two mutations and that of corresponding cDNA from the healthy control were expressed in E. coll. The secondary structures of recombinant polypeptides were analyzed by circular dichroism (CD) spectroscopy. Results CD spectra of healthy control exhibited a negative peak near 208 nm whereas that of TBMN patient with FSGS exhibited a negative peak near 220 nm. Furthermore, the magnitude of the negative peak of this patient decreased as compared with that of healthy control. CD spectra of pure TBMN control was slightly changed with the negative peak remaining near 208 run and the magnitude slightly decreased as compared with that of healthy control. In addition, the secondary structure of pelypeptide from healthy control was composed of about 1/4 α-helix and 1/4 β-sheet, whereas that from the patient presented about 1/3 α-helix without any β-sheet. The secondary structure of polypeptide from pure TBMN control was almost the same as the healthy control, except a shght reduction of α-helix and a slight increase of β-sheet. Conclusions Although the glycine substitutions exists in the nearby domain of α4 (Ⅳ)chain, the TBMN patient complicating FSGS with severe phenotype and g. 1214G>A mutation and the pure TBMN control with the mild phenotype and g. 1550G>A mutation are revealed with different secondary structures of α4 (Ⅳ)chain. Moreover, the secondary structure change of α4 (Ⅳ) chain is consistent with their corresponding phenotype severity.
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Objective To elucidate whether focal segmental glomerulosclerosis (FSGS) is a secondary development of the COL4-linked thin basement membrane nephropathy (TBMN) or the primary FSGS produces thin glomerular basement membrane (GBM). Methods The family members presented microscopic hematuria,increasing proteinuria with the years and a dual pathological diagnosis of FSGS and TBMN was made in the proband.DNA linkage analysis at locus 2q36-37 that contains the COL4A3/COL4A4 genes was performed with polymorphic micmsateilite markers D2S434,D2S279,D2S1370,D2S256 and D2S427.Haplotypes were constructed at the COL4A3/COL4A4 loci for affected and unaffected family members.All exons of COL4A3 and COL4A4 genes were screened for mutations in the proband.Mutation screening was also performed for NPHS1,NPHS2,CD2AP,WTI,TRPC6 and ACTN4 to exclude familial FSGS.Mutation or polymorphism found in the family were examined in 50 healthy controls. Results In this family hematuria segregated with the 55224 haplotype at the COL4A3/COL4A4 locus.G to A substitution at nucleotide 1214 resulting in an glycine being replaced by glutamate (G405E) was demonstrated for the first time in cxon 20 of COL4A4 gene.G4OSE was present in all four members of the family with hematuria but not in the seven unaffected family members nor in 50 healthy controls.A novel polymorphism segregating with hematuria (IVS1-4C＞T in exon 2 ofCOL4A3) was also found which was only present in all four affected family members but not in the seven unaffected family members. No mutations were demonstrated in FSGS associated genes,however,a novel SNP (R268Q),which distributed with the disease ineompletely,was described in the NPHS1 gene coding nephrin,the podocyte slit diaphragm protein. Conclusions In this family,FSGS occurres on the basis of TBMN.Maybe the particular COL4A3/COL4A4 mutation and polymorphism work together to develop proteinuria and eventually leading to FSGS.But whether the mutation and the polymorphism segregating with the disease predispose to develop FSGS in TBMN patients is required further study.