Autosomal dominant Alport syndrome: molecular analysis of the COL4A4 gene and clinical outcome

Marcocci, Elena; Uliana, Vera; Bruttini, Mirella; Artuso, Rosangela; Silengo, Margherita; Zerial, Marlenka; Bergesio, Franco; Amoroso, Antonio; Savoldi, Silvana; Pennesi, Marco; Giachino, Daniela; Rombolà, Giuseppe; Fogazzi, Giovanni B.; Rosatelli, C; Martinhago, Ciro Dresch; Carmellini, Mario; Mancini, R. C.; Costanzo, Giuseppina Di; Longo, Ilaria; Renieri, Alessandra; Mari, Francesca

doi:10.1093/ndt/gfn681

Cited by 79 publications

(70 citation statements)

References 21 publications

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“…The mutation sites were scattered throughout the genes with no accumulation in any specific region as in the previous study (10). Broad differences in phenotypes were observed among unrelated families, even among families with identical variants, and we were unable to establish any genotype-phenotype correlations in this cohort.…”

Section: Discussionmentioning

confidence: 58%

“…A recent study using next generation sequencing (NGS) analysis revealed high proportions of mutations in COL4A3 and COL4A4 and a higher incidence of ADAS than previously reported (6). However, studies of ADAS are limited, and the clinical phenotype and genetic and pathologic backgrounds remain unclear (7)(8)(9)(10)(11)(12). In this study, we provide the first clarification of the genetic, clinical, and pathologic backgrounds of ADAS in a relatively large number of patients.…”

Section: Introductionmentioning

confidence: 74%

“…Marcocci et al (10) reported that 13.3% of patients with ADAS developed sensorineural hearing loss and that only one developed bilateral cataract, which was assumed to be caused by postrenal transplantation steroid treatment. Jais et al (19) reported hearing loss and specific ocular changes in 79% and 35.2%, respectively, among men with XLAS, whereas Oka et al (18) reported hearing loss in 40% and ocular lesions in 10% of Japanese patients with ARAS.…”

Section: Discussionmentioning

confidence: 99%

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Genetic, Clinical, and Pathologic Backgrounds of Patients with Autosomal Dominant Alport Syndrome

Kamiyoshi

Nozu

et al. 2016

CJASN

102

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Background and objectives Alport syndrome comprises a group of inherited heterogeneous disorders involving CKD, hearing loss, and ocular abnormalities. Autosomal dominant Alport syndrome caused by heterozygous mutations in collagen 4A3 and/or collagen 4A4 accounts for ,5% of patients. However, the clinical, genetic, and pathologic backgrounds of patients with autosomal dominant Alport syndrome remain unclear.Design, setting, participants, & measurements We conducted a retrospective analysis of 25 patients with genetically proven autosomal dominant Alport syndrome and their family members (a total of 72 patients) from 16 unrelated families. Patients with suspected Alport syndrome after pathologic examination who were referred from anywhere in Japan for genetic analysis from 2006 to 2015 were included in this study. Clinical, laboratory, and pathologic data were collected from medical records at the point of registration for genetic diagnosis. Genetic analysis was performed by targeted resequencing of 27 podocyte-related genes, including Alport-related collagen genes, to make a diagnosis of autosomal dominant Alport syndrome and identify modifier genes or double mutations. Clinical data were obtained from medical records.Results The median renal survival time was 70 years, and the median age at first detection of proteinuria was 17 years old. There was one patient with hearing loss and one patient with ocular lesion. Among 16 patients who underwent kidney biopsy, three showed FSGS, and seven showed thinning without lamellation of the glomerular basement membrane. Five of 13 detected mutations were reported to be causative mutations for autosomal recessive Alport syndrome in previous studies. Two families possessed double mutations in both collagen 4A3 and collagen 4A4, but no modifier genes were detected among the other podocyte-related genes.Conclusions The renal phenotype of autosomal dominant Alport syndrome was much milder than that of autosomal recessive Alport syndrome or X-linked Alport syndrome in men. It may, thus, be difficult to make an accurate diagnosis of autosomal dominant Alport syndrome on the basis of clinical or pathologic findings. No modifier genes were identified among the known podocyte-related genes.

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Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

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Genetic, Clinical, and Pathologic Backgrounds of Patients with Autosomal Dominant Alport Syndrome

Kamiyoshi

Nozu

et al. 2016

CJASN

102

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“…In this latter form of AS, women and men are equally affected and usually progress to ESRF later than in the autosomal recessive form. [8][9][10] The frequency of each form of AS is estimated to be 80%-85% for X-linked AS, 15% for autosomal recessive AS, and 1%-5% for autosomal dominant AS. 11 However, these numbers may be skewed, because most series with molecular analysis are limited to the sequencing of COL4A5.…”

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confidence: 99%

Improving Mutation Screening in Familial Hematuric Nephropathies through Next Generation Sequencing

Morinière¹,

Dahan

Hilbert

et al. 2014

Journal of the American Society of Nephrology

132

131

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Alport syndrome is an inherited nephropathy associated with mutations in genes encoding type IV collagen chains present in the glomerular basement membrane. COL4A5 mutations are associated with the major X-linked form of the disease, and COL4A3 and COL4A4 mutations are associated with autosomal recessive and dominant forms (thought to be involved in 15% and 1%-5% of the families, respectively) and benign familial hematuria. Mutation screening of these three large genes is time-consuming and expensive. Here, we carried out a combination of multiplex PCR, amplicon quantification, and next generation sequencing (NGS) analysis of three genes in 101 unrelated patients. We identified 88 mutations and 6 variations of unknown significance on 116 alleles in 83 patients. Two additional indel mutations were found only by secondary Sanger sequencing, but they were easily identified retrospectively with the webbased sequence visualization tool Integrative Genomics Viewer. Altogether, 75 mutations were novel. Sequencing the three genes simultaneously was particularly advantageous as the mode of inheritance could not be determined with certainty in many instances. The proportion of mutations in COL4A3 and COL4A4 was notably high, and the autosomal dominant forms of Alport syndrome appear more frequently than reported previously. Finally, this approach allowed the identification of large COL4A3 and COL4A4 rearrangements not described previously. We conclude that NGS is efficient, reduces screening time and cost, and facilitates the provision of appropriate genetic counseling in Alport syndrome.

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“…Approximately 80% of cases demonstrate an X-linked inheritance (X-AS) and are caused by mutations in the COL4A5 gene (3,4); 15%-20% of cases are transmitted with an autosomalrecessive mode and are caused by homozygous or compound heterozygous mutations in the COL4A3 or COL4A4 genes (5,6). Finally, a minority of cases are caused by specific mutations in the COL4A3 or COL4A4 genes and demonstrate an autosomaldominant transmission (6,7,8,9). The exact prevalence of autosomal-dominant AS is still unknown, but it could be higher than previously reported; recent technical advances in the molecular diagnosis of AS will probably help define the relative contribution of these forms (10).…”

Section: Introductionmentioning

confidence: 99%

Prognostic Value of Glomerular Collagen IV Immunofluorescence Studies in Male Patients with X-Linked Alport Syndrome

Massella

Gangemi

Giannakakis

et al. 2013

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives X-linked Alport syndrome (X-AS) is caused by mutations of the COL4A5 gene, which encodes for the collagen IV a5 chain (a5 [COLIV]), resulting in structural and functional abnormalities of the glomerular basement membrane (GBM) and leading to CKD. The aim of the present study was to evaluate the prognostic value of residual collagen IV chain expression in the GBM of patients with X-AS.Design, setting, participants, & measurements The medical records of 22 patients with X-AS from 21 unrelated families collected between 1987 and 2009 were reviewed (median age at last follow-up, 19.9 years; range, 5.4-35.1 years); GBM expression of a1, a3, and a5(COLIV) chains was assessed by immunofluorescence microscopy.

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Autosomal dominant Alport syndrome: molecular analysis of the COL4A4 gene and clinical outcome

Cited by 79 publications

References 21 publications

Genetic, Clinical, and Pathologic Backgrounds of Patients with Autosomal Dominant Alport Syndrome

Genetic, Clinical, and Pathologic Backgrounds of Patients with Autosomal Dominant Alport Syndrome

Improving Mutation Screening in Familial Hematuric Nephropathies through Next Generation Sequencing

Prognostic Value of Glomerular Collagen IV Immunofluorescence Studies in Male Patients with X-Linked Alport Syndrome

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