Negative Staining for COL4A5 Correlates With Worse Prognosis and More Severe Ultrastructural Alterations in Males With Alport Syndrome

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Abstract

Introduction

Alport syndrome (AS) is a genetic disorder characterized by progressive hematuric nephropathy with or without sensorineural hearing loss and ocular lesions. Previous studies on AS included mostly children.

Methods

To determine the prognostic value of loss of staining for collagen type IV alpha 5 (COL4A5) and its relationship with the ultrastructural glomerular basement membrane alterations, we performed direct immunofluorescence using a mixture of fluorescein isothiocyanate-conjugated and Texas-red conjugated antibodies against COL4A5 and COL4A2, respectively, on renal biopsies of 25 males with AS (including 16 who were diagnosed in adulthood).

Results

All patients showed normal positive staining of glomerular basement membranes and tubular basement membranes for COL4A2. Of the 25 patients, 10 (40%) patients showed loss of staining for COL4A5 (including 89% of children and 13% of adults) and the remaining 15 (60%) had intact staining for COL4A5. Compared with patients with intact staining for COL4A5, those with loss of staining had more prominent ultrastructural glomerular basement membrane alterations and were younger at the time of biopsy. By Kaplan-Meier survival analysis and Cox regression analysis, loss of staining for COL4A5 predicted earlier progression to overt proteinuria and stage 2 chronic kidney disease or worse. By multivariate Cox regression analysis, loss of staining for COL4A5 was an independent predictor of the development of overt proteinuria and stage 2 chronic kidney disease or worse.

Discussion

Thus, the COL4A5 expression pattern has an important prognostic value and it correlates with the severity of ultrastructural glomerular basement membrane alterations in males with AS. Loss of COL4A5 staining is uncommon in patients with AS diagnosed in their adulthood.

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Most cited references 19

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Genotype-phenotype correlation in X-linked Alport syndrome.

Mir Reza Bekheirnia, Berenice Reed, Martin C Gregory … (2010)

Mutations in the COL4A5 gene cause X-linked Alport syndrome (XLAS). Understanding the correlation between clinical manifestations and the underlying mutations adds prognostic value to genetic testing, which is increasingly available. Our aim was to determine the association between genotype and phenotype in 681 affected male participants with XLAS from 175 US families. Hearing loss and ocular changes were present in 67 and 30% of participants, respectively. Average age of participants at onset of ESRD was 37 years for those with missense mutations, 28 years for those with splice-site mutations, and 25 years for those with truncating mutations (P < 0.0001). We demonstrated a strong relationship between mutation position and age at onset of ESRD, with younger age at onset of ESRD associated with mutations at the 5' end of the gene (hazard ratio 0.766 [95% confidence interval 0.694 to 0.846] per 1000 bp toward the 3' end; P < 0.0001). Affected participants with splice mutations or truncating mutations each had two-fold greater odds of developing eye problems than those with missense mutations; development of hearing impairment showed a similar trend. Hearing loss and ocular changes associated with mutations located closer to the 5; end of the gene. These strong genotype-phenotype correlations could potentially help in the evaluation and counseling of US families with XLAS.

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X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males.

J Hertz, Willem M de Vos, M. Sanak … (2000)

Alport syndrome (AS) is a type IV collagen hereditary disease characterized by the association of progressive hematuric nephritis, hearing loss, and, frequently, ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease. Considerable allelic heterogeneity has been observed. A "European Community Alport Syndrome Concerted Action" has been established to delineate accurately the AS phenotype and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of the 401 male patients belonging to the 195 families with COL4A5 mutation are presented. All male patients were hematuric, and the rate of progression to end-stage renal failure and deafness was mutation-dependent. Large deletions, non-sense mutations, or small mutations changing the reading frame conferred to affected male patients a 90% probability of developing end-stage renal failure before 30 yr of age, whereas the same risk was of 50 and 70%, respectively, in patients with missense or splice site mutation. The risk of developing hearing loss before 30 yr of age was approximately 60% in patients with missense mutations, contrary to 90% for the other types of mutations. The natural history of X-linked AS and correlations with COL4A5 mutations have been established in a large cohort of male patients. These data could be used for further evaluation of therapeutic approaches.

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MYO1E mutations and childhood familial focal segmental glomerulosclerosis.

Ramona Maranta, Paraskevas Iatropoulos, Simona Buelli … (2011)

Focal segmental glomerulosclerosis is a kidney disease that is manifested as the nephrotic syndrome. It is often resistant to glucocorticoid therapy and progresses to end-stage renal disease in 50 to 70% of patients. Genetic studies have shown that familial focal segmental glomerulosclerosis is a disease of the podocytes, which are major components of the glomerular filtration barrier. However, the molecular cause in over half the cases of primary focal segmental glomerulosclerosis is unknown, and effective treatments have been elusive. We performed whole-genome linkage analysis followed by high-throughput sequencing of the positive-linkage area in a family with autosomal recessive focal segmental glomerulosclerosis (index family) and sequenced a newly discovered gene in 52 unrelated patients with focal segmental glomerulosclerosis. Immunohistochemical studies were performed on human kidney-biopsy specimens and cultured podocytes. Expression studies in vitro were performed to characterize the functional consequences of the mutations identified. We identified two mutations (A159P and Y695X) in MYO1E, which encodes a nonmuscle class I myosin, myosin 1E (Myo1E). The mutations in MYO1E segregated with focal segmental glomerulosclerosis in two independent pedigrees (the index family and Family 2). Patients were homozygous for the mutations and did not have a response to glucocorticoid therapy. Electron microscopy showed thickening and disorganization of the glomerular basement membrane. Normal expression of Myo1E was documented in control human kidney-biopsy specimens in vivo and in glomerular podocytes in vitro. Transfection studies revealed abnormal subcellular localization and function of the A159P-Myo1E mutant. The Y695X mutation causes loss of calmodulin binding and of the tail domains of Myo1E. MYO1E mutations are associated with childhood-onset, glucocorticoid-resistant focal segmental glomerulosclerosis. Our data provide evidence of a role of Myo1E in podocyte function and the consequent integrity of the glomerular filtration barrier.

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Author and article information

Contributors

Samih H. Nasr

Journal

Journal ID (nlm-ta): Kidney Int Rep

Journal ID (iso-abbrev): Kidney Int Rep

Title: Kidney International Reports

Publisher: Elsevier

ISSN (Electronic): 2468-0249

Publication date PMC-release: 29 September 2016

Publication date Collection: January 2017

Publication date (Electronic): 29 September 2016

Volume: 2

Issue: 1

Pages: 44-52

Affiliations

[1 ]Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA

[2 ]Division of Nephrology, Columbia University, College of Physicians and Surgeons, New York, New York, USA

[3 ]Nephrology Section, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia

[4 ]Permanente Medical Group, Oakland, California, USA

[5 ]Division of Pediatric Nephrology, Mayo Clinic, Rochester, Minnesota, USA

[6 ]Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA

Author notes

[∗ ] Correspondence: Samih H. Nasr, Division of Anatomic Pathology, Mayo Clinic, Hilton 10-20, 200 First Street, SW, Rochester, Minnesota 55905, USA.Division of Anatomic PathologyMayo ClinicHilton 10-20, 200 First Street, SWRochesterMinnesota 55905USA nasr.samih@ 123456mayo.edu

Article

Publisher ID: S2468-0249(16)30135-8

DOI: 10.1016/j.ekir.2016.09.056

PMC ID: 5678677

PubMed ID: 29142939

SO-VID: 24498dad-a9ee-4703-a357-3ad29f068642

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Negative Staining for COL4A5 Correlates With Worse Prognosis and More Severe Ultrastructural Alterations in Males With Alport Syndrome

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Abstract

Introduction

Methods

Results

Discussion

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Electron Channelling Contrast Imaging (ECCI)

Most cited references 19

Genotype-phenotype correlation in X-linked Alport syndrome.

X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males.

MYO1E mutations and childhood familial focal segmental glomerulosclerosis.

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