COL4A5 genotypes and clinical characteristics of children with Alport syndrome / 中国当代儿科杂志

OBJECTIVES@#To investigate the genotypes of the pathogenic gene COL4A5 and the characteristics of clinical phenotypes in children with Alport syndrome (AS).@*METHODS@#A retrospective analysis was performed for the genetic testing results and clinical data of 19 AS children with COL4A5 gene mutations.@*RESULTS@#Among the 19 children with AS caused by COL4A5 gene mutations, 1 (5%) carried a new mutation of the COL4A5 gene, i.e., c.3372A>G(p.P1124=) and presented with AS coexisting with IgA vasculitis nephritis; 3 children (16%) had large fragment deletion of the COL4A5 gene, among whom 2 children (case 7 had a new mutation site of loss51-53) had gross hematuria and albuminuria at the onset, and 1 child (case 13 had a new mutation site of loss3-53) only had microscopic hematuria, while the other 15 children (79%) had common clinical phenotypes of AS, among whom 7 carried new mutations of the COL4A5 gene. Among all 19 children, 3 children (16%) who carried COL4A5 gene mutations also had COL4A4 gene mutations, and 1 child (5%) had COL4A3 gene mutations. Among these children with double gene mutations, 2 had gross hematuria and proteinuria at the onset.@*CONCLUSIONS@#This study expands the genotype and phenotype spectrums of the pathogenic gene COL4A5 for AS. Children with large fragment deletion of the COL4A5 gene or double gene mutations of COL4A5 with COL4A3 or COL4A4 tend to have more serious clinical manifestations.

Genetic and clinical analysis of a pedigree affected with X-linked dominant Alport syndrome due to a novel variant of COL4A5 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a Chinese pedigree affected with X-linked hereditary Alport syndrome.@*METHODS@#Next generation sequencing was carried out for the pedigree. Candidate variant was validated by Sanger sequencing. Pathological changes of renal basement membrane and expression of COL4A5 protein were analyzed by renal biopsy and immunofluorescence assay, respectively.@*RESULTS@#All patients from the pedigree manifested progressive renal damage, gross hematuria, proteinuria and nephrotic syndrome. Renal biopsy of the proband revealed thickening of the basement membrane. No expression of the COL4A5 gene was detected by immunofluorescence. High-throughput sequencing and Sanger sequencing indicated that the proband has carried a c.3706delC (p.1236Pfs*69) variant in exon 41 of the COL4A5 gene. The same variant was also found in his mother and two brothers whom were similarly affected.@*CONCLUSION@#The novel c.3706delC (p.1236Pfs*69) variant of the COL4A5 gene probably underlay the pathogenesis of X-linked hereditary Alport syndrome in this pedigree. Above findings have enriched the spectrum of COL4A5 gene variants and provided a basis for the diagnosis and genetic counseling for the pedigree.

Analysis of genetic variant in a child with autosomal recessive Alport syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a pedigree affected with Alport syndrome.@*METHODS@#Next generation sequencing and Sanger sequencing was applied to detect potential variants of the COL4A3, COL4A4 and COL4A5 genes among members from the pedigree and 100 unrelated healthy controls.@*RESULTS@#The proband and his twin brother were found to carry two novel variants, namely c.4953G>A and c.4623C>A, of the COL4A4 gene, which were respectively inherited from her father and mother. The same variants were not detected among the 100 healthy controls and medical literature. Based on the guidelines of the American College of Medical Genetics and Genomics, both the c.4953G>A and c.4623C>A variants were predicted to be pathogenic (PVS1+PM2_supporting+PP1).@*CONCLUSION@#The c.4953G>A and c.4623C>A variants of the COLA4A gene probably underlay the Alport syndrome in this pedigree. Above finding has enriched the spectrum of COLA4A gene variants.

Identifi cation of novel variants in the COL4A4 gene in Korean patients with thin basement membrane nephropathy.

Background & objectives: The α4 chain of the type 4 collagen family is an important component of the glomerular basement membrane (GBM) in the kidney. It is encoded by the COL4A4 gene, and mutations of this gene are known to be associated with thin basement membrane nephropathy (TBMN). To better understand the contribution of variants in the COL4A4 gene to TBMN, we investigated the sequence of the complete COL4A4 gene in 45 Korean patients with TBMN. Method: Genomic DNA was obtained from the peripheral blood lymphocytes. For the analysis of the COL4A4 gene, all the exons including splicing sites were amplififi ed by PCR and screened by direct sequencing analysis. Results: Eight novel COL4A4 sequence variants were found in these patients. Two of these variants, G199R and G1606E, were possibly pathogenic variants affecting the phenotype. None of these variants were observed in 286 chromosomes from normal Korean control subjects. In addition, 39 polymorphisms including 7 novel SNPs were identifi ed in this study. Interpretation & conclusion: The frequency of COL4A4 mutations in Korean patients with TBMN is low and the other cases may have mutations in other genes like COL4A3. Screening of the COL4A3 gene and fi nding a novel causative gene for TBMN will help clarify the pathogenesis of this disorder and perhaps for distinguishing TBMN from Alport syndrome.

Regulation of Type IV Collagen alpha Chains of Glomerular Epithelial Cells in Diabetic Conditions

An early feature of diabetic nephropathy is the alteration of the glomerular basement membrane (GBM), which may result in microalbuminuria, subsequent macroproteinuria, and eventual chronic renal failure. Although type IV collagen is the main component of thickened GBM in diabetic nephropathy, cellular metabolism of each alpha chains of type IV collagen has not been well studied. To investigate the regulation of alpha(IV) chains in diabetic conditions, we examined whether glucose and advanced glycosylation endproduct (AGE) regulate the metabolism of each alpha(IV) chains in the diabetic tissue and glomerular epithelial cells (GEpC). Glomerular collagen alpha3(IV) and alpha5(IV) chains protein were higher and more intense in immunofluorescence staining according to diabetic durations compared to controls. In vitro, mainly high glucose and partly AGE usually increased total collagen protein of GEpC by [3H]-proline incorporation assay and each alpha(IV) chain proteins including alpha1(IV), alpha3(IV), and alpha5(IV) in time-dependent and subchain-specific manners. However, the changes of each alpha(IV) chains mRNA expression was not well correlated to the those of each chain proteins. The present findings suggest that the metabolism of individual alpha(IV) chains of GBM is differentially regulated in diabetic conditions and those changes might be induced not only by transcriptional level but also by post-translational modifications.

Revisão sobre a perda auditiva na Síndrome de Alport, analisando os aspectos clínicos, genéticos e biomoleculares / Revision about hearing loss in the Alport's syndrome, analyzing the clinical, genetic and bio-molecular aspects

A Síndrome de Alport é uma desordem hereditária, caracterizada por hematúria, freqüentemente levando à falência renal. Pode ser acompanhada de alterações extra-renais, tais como: perda auditiva (PA) sensório-neural e alterações oculares. São descritas formas dominantes ligadas ao X, devidas às mutações no lócus COL4A5 e uma forma autossômica recessiva resultando de mutações no lócus COL4A3 ou COL4A4. Ainda foi sugerido um tipo autossômico dominante de SA. A doença decorre de alterações nas cadeias de colágeno tipo IV e os sintomas refletem o comprometimento da membrana basal de vários órgãos. As redes a3.a4.a5(IV) ocorrem no rim, na cóclea e no olho. O objetivo foi caracterizar a PA neste grupo de pacientes. Quando o quadro progride para o estágio final de falência renal, o melhor método de tratamento é o transplante, que tem contribuído para o aumento da sobrevida. Nesta revisão bibliográfica, observamos que: 1. A SA caracteriza-se por hematúria, que evolui para falência renal e pode ser acompanhada de manifestações extra-renais. A PA é um achado extra-renal freqüente e um dos primeiros sintomas na SA, sendo um fator relevante para o prognóstico da evolução da doença renal; 2. A SA é genética e decorre da alteração das cadeias do colágeno tipo IV nas membranas basais; 3. A perda auditiva na SA é sensório-neural, de intensidade variável, progressiva e simétrica. Acomete as freqüências médias e altas; 4. Na investigação das perdas auditivas, o torrinolaringologista deve incluir um exame de urina. É fundamental que o otologista atue no acompanhamento deste grupo de pacientes.

Alport Syndrome is a genetic disorder characterized by hematuria, which often leads to renal failure. It may also be accompanied by extra-renal alterations, such as: sensorineural hearing loss, and ocular abnormalities. Dominant forms related to the X chromosome and caused by mutations in the locus COL4A5 have been described, as well as an autossomic recessive form resulting from mutations in the locus COL4A3 or COL4A4. An autossomic dominant type of AS has also been reported. The disease is caused by changes in the collagen type IV chains, where symptoms reflect the damage to the basal membrane of several organs. The alpha3.alpha4.alpha5(IV) networks are found in the kidneys, cochlea and eyes. The objective was to characterize AS in this group of patients. In the current literature review it was found that: 1. AS is characterized by hematuria that may develop into renal failure and can also be accompanied by extra-renal manifestations. Hearing loss is a frequent extra-renal finding and one of the first symptoms of AS, therefore representing a relevant factor in the prognosis of the renal disease; 2. It is a genetic disorder resulting from abnormalities in the chains of collagen type IV in the basal membranes; 3. The hearing loss in AS is typically sensorineural with variable intensities, progressive and symmetrical, affecting middle and high frequencies; 4. Otolaryngologists should include a urine test in the SNHL work-up. It is essential to have an otologist involved in the treatment of these patients.