Novel exon nucleotide substitution at the splice junction causes a neonatal Marfan syndrome

Chao, Sheau Chiou; Chen, J. S.; Tsai, Chin-Chu; Lin, Jui Yang; Lin, Yu‐Jia; Sun, Han

doi:10.1111/j.1399-0004.2009.01337.x

Cited by 10 publications

(3 citation statements)

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“…Truncated transcripts are usually degraded by the nonsense-mediated mRNA decay (NMD) mechanism [ 17 ], which would then result in reduced or no expression of truncated fibrillin-1 thus ameliorating negative effects of microfibrils on ECM. Splice site mutations are also frequent in MFS [ 18 , 19 ]. Infrequently, large genomic deletions involving single or multiple exons of the FBN1 gene, as well as whole FBN1 deletions, have been identified [ 20 – 22 ].…”

Section: Introductionmentioning

confidence: 99%

Qualitative and quantitative analysis of FBN1 mRNA from 16 patients with Marfan Syndrome

et al. 2015

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BackgroundPathogenic mutations in FBN1, encoding the glycoprotein, fibrillin-1, cause Marfan syndrome (MFS) and related connective tissue disorders. In the present study, qualitative and quantitative effects of 16 mutations, identified in FBN1 in MFS patients with systematically described phenotypes, were investigated in vitro.MethodsQualitative analysis was performed with reverse transcription-PCR (RT-PCR) and gel electrophoresis, and quantitative analysis to determine the FBN1 mRNA levels in fibroblasts from the 16 patients with MFS was performed with real-time PCR.ResultsQualitative analysis documented that the mutations c.4817-2delA and c.A4925G led to aberrant FBN1 mRNA splicing leading to in frame deletion of exon 39 and in exon 39, respectively. No difference in the mean FBN1 mRNA level was observed between the entire group of cases and controls, nor between the group of patients with missense mutations and controls. The mean expression levels associated with premature termination codon (PTC) and splice site mutations were significantly lower than the levels in patients with missense mutations. A high level of FBN1 mRNA in the patient with the missense mutation c.G2447T did not segregate with the mutation in three of his first degree relatives. No association was indicated between the FBN1 transcript level and specific phenotypic manifestations.ConclusionsAbnormal FBN1 transcripts were indicated in fibroblasts from patients with the splice site mutation c.4817-2delA and the missense mutation c.A4925G. While the mean FBN1 mRNA expression level in fibroblasts from patients with splice site and PTC mutations were lower than the mean level in patients with missense mutations and controls, inter-individual variability was high. The observation that high level of FBN1 mRNA in the patient with the missense mutation c.G2447T did not segregate with the mutation in the family suggests that variable expression of the normal FBN1 allele may contribute to explain the variability in FBN1 mRNA level.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0260-4) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Qualitative and quantitative analysis of FBN1 mRNA from 16 patients with Marfan Syndrome

et al. 2015

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“…The majority of variants clearly inactivate the gene by creating an early stop of translation by introducing either a nonsense, or a frameshift variant. Some mutations, like c.1266G>C and c.380G>A, are located near the splice sites, and may therefore alter splicing and disrupt the reading frame [Chao et al, ; Sun et al, ]. Other variants are predicted to generate a new splice site by Human Splicing Finder [Desmet et al, ] (http://www.umd.be/HSF/, date July 06, 2012).…”

Section: Discussionmentioning

confidence: 99%

Autosomal Recessive Spinocerebellar Ataxia 7 (SCAR7) is Caused by Variants inTPP1, The Gene Involved in Classic Late-Infantile Neuronal Ceroid Lipofuscinosis 2 Disease (CLN2 Disease)

et al. 2013

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Spinocerebellar ataxias are phenotypically, neuropathologically, and genetically heterogeneous. The locus of autosomal recessive spinocerebellar ataxia type 7 (SCAR7) was previously linked to chromosome band 11p15. We have identified TPP1 as the causative gene for SCAR7 by exome sequencing. A missense and a splice site variant in TPP1, cosegregating with the disease, were found in a previously described SCAR7 family and also in another patient with a SCAR7 phenotype. TPP1, encoding the tripeptidyl-peptidase 1 enzyme, is known as the causative gene for late infantile neuronal ceroid lipofuscinosis disease 2 (CLN2 disease). CLN2 disease is characterized by epilepsy, loss of vision, ataxia, and a rapidly progressive course, leading to early death. SCAR7 patients showed ataxia and low activity of tripeptidyl-peptidase 1, but no ophthalmologic abnormalities or epilepsy. Also, the slowly progressive evolution of the disease until old age and absence of ultra structural curvilinear profiles is different from the known CLN2 phenotypes. Our findings now expand the phenotypes related to TPP1-variants to SCAR7. In spite of the limited sample size and measurements, a putative genotype-phenotype correlation may be drawn: we hypothesize that loss of function variants abolishing TPP1 enzyme activity lead to CLN2 disease, whereas variants that diminish TPP1 enzyme activity lead to SCAR7.

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“…The most common are mutations affecting the wild-type splice sites, leading to exon skipping [Nijbroek et al, 1995;Hutchinson et al, 2001]. Occasionally, activation of a cryptic splice site within the exon or intron, causing, respectively, a partial exon deletion [McGrory and Cole, 1999] or a partial intron insertion or complete intron retention [Hutchinson et al, 2001;Chao et al, 2010], have been described. To the best of our knowledge, this is only the second identification of a pseudo-exon in FBN1.…”

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AnFBN1Deep Intronic Mutation in a Familial Case of Marfan Syndrome: An Explanation for Genetically Unsolved Cases?

et al. 2014

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Marfan syndrome (MFS) is caused by mutations in the FBN1 (fibrillin-1) gene, but approximately 10% of MFS cases remain genetically unsolved. Here, we report a new FBN1 mutation in an MFS family that had remained negative after extensive molecular genomic DNA FBN1 testing, including denaturing high-performance liquid chromatography, Sanger sequencing, and multiplex ligation-dependent probe amplification. Linkage analysis in the family and cDNA sequencing of the proband revealed a deep intronic point mutation in intron 56 generating a new splice donor site. This mutation results in the integration of a 90-bp pseudo-exon between exons 56 and 57 containing a stop codon, causing nonsense-mediated mRNA decay. Although more than 90% of FBN1 mutations can be identified with regular molecular testing at the genomic level, deep intronic mutations will be missed and require cDNA sequencing or whole-genome sequencing.

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Novel exon nucleotide substitution at the splice junction causes a neonatal Marfan syndrome

Cited by 10 publications

References 32 publications

Qualitative and quantitative analysis of FBN1 mRNA from 16 patients with Marfan Syndrome

Qualitative and quantitative analysis of FBN1 mRNA from 16 patients with Marfan Syndrome

Autosomal Recessive Spinocerebellar Ataxia 7 (SCAR7) is Caused by Variants inTPP1, The Gene Involved in Classic Late-Infantile Neuronal Ceroid Lipofuscinosis 2 Disease (CLN2 Disease)

AnFBN1Deep Intronic Mutation in a Familial Case of Marfan Syndrome: An Explanation for Genetically Unsolved Cases?

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