X-linked Alport syndrome associated with a synonymous p.Gly292Gly mutation alters the splicing donor site of the type IV collagen alpha chain 5 gene

Fu, Xue Jun; Nozu, Kandai; Eguchi, Aya; Nozu, Yoshimi; Morisada, Naoya; Shono, Atsuko; Taniguchi‐Ikeda, Mariko; Shima, Yuko; Nakanishi, Koichi; Vořechovský, Igor; Iijima, Kazumoto

doi:10.1007/s10157-015-1197-9

Cited by 18 publications

(20 citation statements)

References 14 publications

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“…Similar findings have been reported in other disorders, (26)(27)(28)(29)(30)(31)(32) also including skeletal defects (33)(34)(35) ; nonetheless, the contribution of synonymous mutations to human pathologies is likely highly underestimated at present. Although performing functional evaluations of all the synonymous changes in an individual exome is not cost-effective, it might be worth assessing the effect of those located in genes already known to be associated with diseases.…”

Section: Discussionsupporting

confidence: 84%

Synonymous Mutations Add a Layer of Complexity in the Diagnosis of Human Osteopetrosis

Palagano

Susani

Menale

et al. 2016

Journal of Bone and Mineral Research

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Autosomal recessive osteopetroses (AROs) are rare, genetically heterogeneous skeletal diseases with increased bone density that are often lethal if left untreated. A precise molecular classification is relevant for the patient's management, because in some subgroups hematopoietic stem cell transplantation (HSCT), which is the only curative therapy, is contraindicated. In two unrelated ARO patients, the molecular analysis revealed the presence of a synonymous variant in known ARO genes, namely in the TCIRG1 gene in one patient and in the CLCN7 in the other patient, predicted to impact on the splicing process. In the latter case, sequencing of the transcript confirmed the splicing defect, whereas in the former, for whom an RNA sample was not available, the defect was reconstructed in vitro by the minigene technology. These results strongly suggest that these synonymous changes were responsible for the disease in our patients. Our findings are novel with respect to ARO and add to the few reports in literature dealing with different diseases, underlining the importance of cDNA analysis for the correct assessment of exonic changes, even when exome sequencing is performed. In particular, we highlight the possibility that at least in some cases ARO is due to synonymous changes, erroneously considered clinically silent, in the genes already described in literature, and suggest carefully reevaluating the sequencing results of these genes when mutations are not found at a first analysis. In addition, with respect to the CLCN7 gene, we suggest that synonymous variants might also contribute to the large spectrum of severity typical of CLCN7-dependent osteopetrosis through more subtle, but not negligible, effects on protein availability and functionality. © 2016 American Society for Bone and Mineral Research.

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Section: Discussionsupporting

confidence: 84%

Synonymous Mutations Add a Layer of Complexity in the Diagnosis of Human Osteopetrosis

Palagano

Susani

Menale

et al. 2016

Journal of Bone and Mineral Research

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“…Among these 41 families, 11 exhibit splicing variants that we have already reported, along with corresponding transcript analysis. 6,7,14 Furthermore, for two families (A43, A302), transcript analysis results have been reported by another group. 15 These cases were included in this study for purposes of genotypephenotype correlation analysis.…”

Section: Abnormal Splicing Patterns Detected In Our Studymentioning

confidence: 62%

Detection of Splicing Abnormalities and Genotype-Phenotype Correlation in X-linked Alport Syndrome

Horinouchi

Nozu

Yamamura

et al. 2018

JASN

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“…With Step 3, we have identified deep intronic variants that lead to cryptic exon insertion by creating novel splicing sites [12, 20]. We have also identified aberrant splicing caused by a so-called “silent variant,” an exonic single-nucleotide substitution that does not change the coding amino acid [22].…”

Section: Gene Testsmentioning

confidence: 99%

A review of clinical characteristics and genetic backgrounds in Alport syndrome

et al. 2018

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Alport syndrome (AS) is a progressive hereditary renal disease that is characterized by sensorineural hearing loss and ocular abnormalities. It is divided into three modes of inheritance, namely, X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, while ADAS and ARAS are caused by those in COL4A3/COL4A4. Diagnosis is conventionally made pathologically, but recent advances in comprehensive genetic analysis have enabled genetic testing to be performed for the diagnosis of AS as first-line diagnosis. Because of these advances, substantial information about the genetics of AS has been obtained and the genetic background of this disease has been revealed, including genotype-phenotype correlations and mechanisms of onset in some male XLAS cases that lead to milder phenotypes of late-onset end-stage renal disease (ESRD). There is currently no radical therapy for AS and treatment is only performed to delay progression to ESRD using nephron-protective drugs. Angiotensin-converting enzyme inhibitors can remarkably delay the development of ESRD. Recently, some new drugs for this disease have entered clinical trials or been developed in laboratories. In this article, we review the diagnostic strategy, genotype-phenotype correlation, mechanisms of onset of milder phenotypes, and treatment of AS, among others.

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X-linked Alport syndrome associated with a synonymous p.Gly292Gly mutation alters the splicing donor site of the type IV collagen alpha chain 5 gene

Abstract: This is the first report of a synonymous COL4A5 substitution being responsible for XLAS. Our findings suggest that transcript analysis should be conducted for the future correct assessment of silent mutations.

Cited by 18 publications

References 14 publications

Synonymous Mutations Add a Layer of Complexity in the Diagnosis of Human Osteopetrosis

Synonymous Mutations Add a Layer of Complexity in the Diagnosis of Human Osteopetrosis

Detection of Splicing Abnormalities and Genotype-Phenotype Correlation in X-linked Alport Syndrome

A review of clinical characteristics and genetic backgrounds in Alport syndrome

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