Dataset Information

Absence of the c.169+50delTAAACAG mutation of SOD1 gene in a sample of keratoconus patients in Brazilian population.

ABSTRACT: OBJECTIVE:To determine the presence of the 7-bp deletion c.169+50delTAAACAG in intron 2 of Superoxide Dismutase-1 gene in keratoconic patients from the State of São Paulo, Brazil, which promotes splicing variations, resulting in non-functional Superoxide Dismutase-1 antioxidant proteins, which may damage the corneal structure. RESULTS:A group of 35 keratoconic patients, from whom 35 peripheral blood samples and 58 samples of corneal fragments were evaluated, and a control group of 89 individuals, from whom 41 blood samples and 149 samples of corneal fragments were collected. After the amplification of DNA fragments by polymerase chain reaction, mutational screening analysis was performed by enzymatic digestion, followed by direct sequencing. The absence of the 7-bp c.169+50delTAAACAG mutation in intron 2 of Superoxide Dismutase-1 gene was detected in the analyzed subjects of the 2 groups, both in the cornea and peripheral blood samples. Then, according to our results, there is no involvement of c.169+50delTAAACAG deletion in the pathogenesis of keratoconus in this population, once it was not detected. But we emphasize that studies involving this deletion must be continued in an attempt to elucidate this issue.

SUBMITTER: Lopes AG

PROVIDER: S-EPMC7346509 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Absence of the c.169+50delTAAACAG mutation of SOD1 gene in a sample of keratoconus patients in Brazilian population.

Lopes Alessandro Garcia AG de Almeida Júnior Gildásio Castello GC Teixeira Ronan Marques RM de Mattos Luiz Carlos LC Brandão de Mattos Cinara Cássia CC Castiglioni Lilian L

BMC research notes 20200709 1

<h4>Objective</h4>To determine the presence of the 7-bp deletion c.169+50delTAAACAG in intron 2 of Superoxide Dismutase-1 gene in keratoconic patients from the State of São Paulo, Brazil, which promotes splicing variations, resulting in non-functional Superoxide Dismutase-1 antioxidant proteins, which may damage the corneal structure.<h4>Results</h4>A group of 35 keratoconic patients, from whom 35 peripheral blood samples and 58 samples of corneal fragments were evaluated, and a control group of ...[more]

PMID: 32646478

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Project description:Purpose:To investigate the presence of the variants of lysyl oxygenase (LOX) and superoxide dismutase 1 (SOD1) genes in Brazilian patients with advanced keratoconus. Methods:Donor genomic DNA extracted from blood samples was screened for 5'UTR, exonic LOX, and SOD1 variants in a subset of 26 patients presenting with advanced keratoconus (KISA > 1000% and I-S > 2.0) by Sanger sequencing. The impact of non-synonymous amino acid changes was evaluated by SIFT, PMUT, and PolyPhen algorithms. The Mutation Taster tool was used to evaluate the potential impact of formation of new donor and acceptor splice sites in the promoter region of affected volunteers carrying sequence variants. A 7-base SOD1 deletion (IVS2 + 50del7bp) previously associated with keratoconus was screened in 140 patients presenting classical keratoconus by gel fragment analysis, and positive samples were sequenced for confirmation. Results:We found an unreported missense variant in LOX exon 6 in one heterozygous patient, leading to substitution of proline with threonine at residue 392 (p. Thr392Pro) of LOX protein sequence. This mutation was predicted to be potentially damaging to LOX protein. Another LOX variant, Arg158Gln, was also detected in another patient but predicted to be non-pathogenic. Two additional new polymorphisms in LOX 5'UTR region (-116C > T and -58C > T) were found in two patients presenting with advanced keratoconus and were predicted to modulate or create donor/acceptor splice sites in LOX transcripts. Additionally, SOD1 deletion was detected in one patient presenting with severe keratoconus, not in control samples. Conclusion:We described three novel LOX polymorphisms identified for the first time in Brazilian patients with advanced keratoconus, as well as a previously described SOD1 deletion strongly associated with keratoconus. A possible role of these variants in modulating transcript levels in the cornea of affected individual requires further investigation.

Project description:BACKGROUND:Mutations in the SLC26A4 gene are associated with Pendred syndrome and autosomal recessive non-syndromic deafness (DFNB4). Both disorders have similar audiologic characteristics: bilateral hearing loss, often severe or profound, which may be associated with abnormalities of the inner ear, such as dilatation of the vestibular aqueduct or Mondini dysplasia. But, in Pendred syndrome (OMIM #274600), with autosomal recessive inheritance, besides congenital sensorineural deafness, goiter or thyroid dysfunctions are frequently present. The aim of this study was to determine whether mutations in SLC26A4 are a frequent cause of hereditary deafness in Brazilian patients. METHODS:Microsatellite haplotypes linked to SLC26A4 were investigated in 68 families presenting autosomal recessive non-syndromic deafness. In the probands of the 16 families presenting segregation consistent with linkage to SLC26A4, Sanger sequencing of the 20 coding exons was performed. In an additional sample of 15 individuals with suspected Pendred syndrome, because of the presence of hypothyroidism or cochleovestibular malformations, the SLC26A4 gene coding region was also sequenced. RESULTS:In two of the 16 families with indication of linkage to SLC26A4, the probands were found to be compound heterozygotes for probably pathogenic different mutations: three novel (c.1003 T?>?G (p. F335 V), c.1553G?>?A (p.W518X), c.2235?+?2 T?>?C (IVS19?+?2 T?>?C), and one already described, c.84C?>?A (p.S28R). Two of the 15 individuals with suspected Pendred syndrome because of hypothyreoidism or cochleovestibular malformations were monoallelic for likely pathogenic mutations: a splice mutation (IVS7?+?2 T?>?C) and the previously described c.1246A?>?C (p.T416P). Pathogenic copy number variations were excluded in the monoallelic cases and in those with normal results after Sanger sequencing. Additional mutations in the SLC26A4 gene or other definite molecular cause for deafness were not identified in the monoallelic patients, after exome sequencing. CONCLUSIONS:Biallelic pathogenic mutations in SLC26A4 explained ~?3% of cases selected because of autosomal recessive deafness. Monoallelic mutations were present in ~?13% of isolated cases of deafness with cochleovestibular malformations or suspected Pendred syndrome. These data reinforce the importance of mutation screening of SLC26A4 in Brazilian subjects and highlight the elevated frequency of monoallelic patients.

Dataset Information

Absence of the c.169+50delTAAACAG mutation of SOD1 gene in a sample of keratoconus patients in Brazilian population.

Publications

Absence of the c.169+50delTAAACAG mutation of SOD1 gene in a sample of keratoconus patients in Brazilian population.

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