Dataset Information

Evaluation of Suspected Autosomal Alport Syndrome Synonymous Variants.

ABSTRACT:

Background

Alport syndrome is an inherited disorder characterized by progressive renal disease, variable sensorineural hearing loss, and ocular abnormalities. Although many pathogenic variants in COL4A3 and COL4A4 have been identified in patients with autosomal Alport syndrome, synonymous mutations in these genes have rarely been identified.

Methods

We conducted in silico splicing analysis using Human Splicing Finder (HSF) and Alamut to predict splicing domain strength and disruption of the sites. Furthermore, we performed in vitro splicing assays using minigene constructs and mRNA analysis of patient samples to determine the pathogenicity of four synonymous variants detected in four patients with suspected autosomal dominant Alport syndrome (COL4A3 [c.693G>A (p.Val231=)] and COL4A4 [c.1353C>T (p.Gly451=), c.735G>A (p.Pro245=), and c.870G>A (p.Lys290=)]).

Results

Both in vivo and in vitro splicing assays showed exon skipping in two out of the four synonymous variants identified (c.735G>A and c.870G>A in COL4A4). Prediction analysis of wild-type and mutated COL4A4 sequences using HSF and Alamut suggested these two variants may lead to the loss of binding sites for several splicing factors, e.g., in acceptor sites and exonic splicing enhancers. The other two variants did not induce aberrant splicing.

Conclusions

This study highlights the pitfalls of classifying the functional consequences of variants by a simple approach. Certain synonymous variants, although they do not alter the amino acid sequence of the encoded protein, can dramatically affect pre-mRNA splicing, as shown in two of our patients. Our findings indicate that transcript analysis should be carried out to evaluate synonymous variants detected in patients with autosomal dominant Alport syndrome.

SUBMITTER: Rossanti R

PROVIDER: S-EPMC9034806 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

Evaluation of Suspected Autosomal Alport Syndrome Synonymous Variants.

Rossanti Rini R Horinouchi Tomoko T Yamamura Tomohiko T Nagano China C Sakakibara Nana N Ishiko Shinya S Aoto Yuya Y Kondo Atsushi A Nagai Sadayuki S Okada Eri E Ishimori Shingo S Nagase Hiroaki H Matsui Satoshi S Tamagaki Keiichi K Ubara Yoshifumi Y Nagahama Masahiko M Shima Yuko Y Nakanishi Koichi K Ninchoji Takeshi T Matsuo Masafumi M Iijima Kazumoto K Nozu Kandai K

Kidney360 20211013 3

<h4>Background</h4>Alport syndrome is an inherited disorder characterized by progressive renal disease, variable sensorineural hearing loss, and ocular abnormalities. Although many pathogenic variants in <i>COL4A3</i> and <i>COL4A4</i> have been identified in patients with autosomal Alport syndrome, synonymous mutations in these genes have rarely been identified.<h4>Methods</h4>We conducted <i>in silico</i> splicing analysis using Human Splicing Finder (HSF) and Alamut to predict splicing domain ...[more]

PMID: 35582193

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Project description:Background and objectivesAlport 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, & measurementsWe 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.ResultsThe 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.ConclusionsThe 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.

Dataset Information

Evaluation of Suspected Autosomal Alport Syndrome Synonymous Variants.

Background

Methods

Results

Conclusions

Publications

Evaluation of Suspected Autosomal Alport Syndrome Synonymous Variants.

Similar Datasets

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