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A Novel Splice-Site Mutation in the ELN Gene Suggests an Alternative Mechanism for Vascular Elastinopathies.

ABSTRACT: The ELN gene encodes elastin, a fundamental protein of the extracellular matrix that confers elasticity to different tissues including blood vessels. The formation of elastin fibers is a complex process involving monomer coacervation and subsequent crosslinking. Mutations in exons 1-29 of the ELN gene have been linked to supravalvular aortic stenosis (SVAS) whereas mutations in exons 30-33 are associated with autosomal dominant cutis laxa (ADCL). This striking segregation has led to the hypothesis that distinct molecular mechanisms underlie both diseases. SVAS is believed to arise through haploinsufficiency while ADCL is hypothesized to be caused by a dominant negative effect. Here, we describe a patient with SVAS harboring a novel splice-site mutation in the last exon of ELN. The location of this mutation is not consistent with current knowledge of SVAS, since all mutations reported in the C-terminus have been found in ADCL patients, and a thorough evaluation did not reveal significant skin involvement in this case. RT-PCR analysis of skin tissue showed that C-terminal mutations in the region can lead to the production of aberrant transcripts through intron retention and activation of cryptic splice sites and suggest that disruption of the very last exon can lead to functional haploinsufficiency potentially related to SVAS.

SUBMITTER: Velandia-Piedrahita CA

PROVIDER: S-EPMC7751611 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A Novel Splice-Site Mutation in the ELN Gene Suggests an Alternative Mechanism for Vascular Elastinopathies.

Velandia-Piedrahita Camilo Andres CA Morel Adrien A Fonseca-Mendoza Dora Janeth DJ Huertas-Quiñones Victor Manuel VM Castillo David D Bonilla Juan Diego JD Hernandez-Toro Camilo José CJ Miranda-Fernández Marta Catalina MC Restrepo Carlos Martin CM Cabrera Rodrigo R

The application of clinical genetics 20201217

The ELN gene encodes elastin, a fundamental protein of the extracellular matrix that confers elasticity to different tissues including blood vessels. The formation of elastin fibers is a complex process involving monomer coacervation and subsequent crosslinking. Mutations in exons 1-29 of the ELN gene have been linked to supravalvular aortic stenosis (SVAS) whereas mutations in exons 30-33 are associated with autosomal dominant cutis laxa (ADCL). This striking segregation has led t ...[more]

PMID: 33364810

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Project description:BACKGROUND:The mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease resulting from the defective activity of the enzyme ?-L-iduronidase (IDUA). The disease has three major clinical subtypes (severe Hurler syndrome, intermediate Hurler-Scheie syndrome and attenuated Scheie syndrome). We aim to identify the genetic variants in MPS I patients and to investigate the effect of the novel splice site mutation on splicing of IDUA- mRNA variability using bioinformatics tools. METHODS:The IDUA mutations were determined in four MPS I patients from four families from Northern Tunisia, by amplifying and sequencing each of the IDUA exons and intron-exon junctions. RESULTS:One novel splice site IDUA mutation, c.1650?+?1G?>?T in intron 11 and two previously reported mutations, p.A75T and p.R555H, were detected. The patients in families 1 and 2 who have the Hurler phenotype were homozygotes for the novel splice site mutation c.1650?+?1G?>?T. The patient in family 3, who also had the Hurler phenotype, was a compound heterozygote for the novel splice site mutation c.1650?+?1G?>?T and for the previously reported missense mutation p.A75T. The patient in family 4 who had the Hurler-Scheie phenotype was a compound heterozygote for the novel splice site mutation c.1650?+?1G?>?T and for the previously reported missense mutation p.R555H. In addition, four known IDUA polymorphisms were identified. Bioinformatics tools allowed us to associate the variant c.1650?+?1G?>?T with the severe clinical phenotype of MPS I. This variant affects the essential nucleotide +?1 (G to T) of the donor splice site of IDUA intron 11. The G?>?T in intron 11 leads to wild type donor site broken with minus 19.97% value compared to normal value with 0%, hence the new splice site acceptor has plus 5.59%. CONCLUSIONS:The present findings indicate that the identified mutations facilitate the accurate carrier detection (genetic counseling of at-risk relatives) and the molecular prenatal diagnosis in Tunisia.

Project description:PURPOSE: To present the ocular findings of a Hungarian family with X-linked juvenile retinoschisis (XLRS) and to reveal a novel putative splice mutation leading to serious truncation of retinoschisin (RS1) protein. Our genetic results were compared to a mouse model of XLRS. METHODS: Complete ophthalmic examinations were performed on five members (two male patients, two female carriers, and one healthy fraternal male twin) of the family. The examinations included optical coherence tomography (OCT) and full-field and multifocal electroretinography (mfERG). OCT and ERG results were compared to the normative database of our laboratory. All exons and the flanking intronic regions of the RS1 gene were amplified by polymerase chain reaction and directly sequenced in all family members and in 50 male controls. RESULTS: Typical microcystic foveal changes were found on fundoscopy and OCT in two male patients. Large foveal and smaller perifoveal cysts were detected by OCT in the inner nuclear layer and another deeper retinal cleavage in the photoreceptor layer. The standard combined b-wave amplitudes and b/a amplitude ratios of full-field ERGs of the male patients were decreased compared with controls, but the typical "negative-type" ERG was not observed. The amplitudes of mfERGs were reduced in all rings but mainly in the central part of the examined retina. Implicit times were delayed across almost the whole testing field. Female carriers and the healthy fraternal twin brother were without any symptoms and had normal clinical examination results, but the implicit times of female carriers were delayed in all rings. DNA sequence analyses revealed a novel putative splice mutation (c.78+1G>C) in the splice donor site of intron 2 in RS1 of two male patients and two female carriers. Mutations were absent in the 50 control samples. CONCLUSIONS: Male patients exhibited typical bilateral foveal retinoschisis in two retinal layers and characteristic ERG changes. The inheritance of the novel putative splice mutation (c.78+1G>C) followed the classic inheritance of an X-linked recessive disease in two male patients and two female obligate carriers. There are two possible ways the c.78+1G>C splice site mutation may lead to frameshift and introduce a premature termination codon at the beginning of exon 3: after activation of the next cryptic splice site by a 10 bp insertion or after exon skipping by a 26 bp deletion. The splice site mutation in the second intron of RS1 identified in these XLRS patients is practically identical to the N-ethyl-N-nitrosourea (ENU) induced splice site mutation in the mouse model of XLRS described by the Tennessee Mouse Genome Consortium. The genetic findings of the mutant mouse model confirm and support our human results.

Project description:PurposeLeber congenital amaurosis (LCA) is one of the most common causes of hereditary blindness in infants. To date, mutations in 13 known genes and at two other loci have been implicated in LCA causation. An examination of the known genes highlights several processes which, when defective, cause LCA, including photoreceptor development and maintenance, phototransduction, vitamin A metabolism, and protein trafficking. In addition, it has been known for some time that defects in sensory cilia can cause syndromes involving hereditary blindness. More recently evidence has come to light that non-syndromic LCA can also be a "ciliopathy."MethodsHere we present a homozygosity mapping analysis in a consanguineous sibship that led to the identification of a mutation in the recently discovered LCA5 gene. Homozygosity mapping was done using Affymetrix 10K Xba I Gene Chip and a 24.5cM region on chromosome 6 (6q12- q16.3) was identified to be significantly homozygous. The LCA5 gene on this region was sequenced and cDNA sequencing also done to characterize the mutation.ResultsA c.955G>A missense mutation in the last base of exon 6 causing disruption of the splice donor site was identified in both the affected sibs. Since there is a second consensus splice donor sequence 5 bp into the adjacent intron, this mutation results in a transcript with a 5 bp insertion of intronic sequence, leading to a frameshift and premature truncation.ConclusionsWe report a missense mutation functionally altering the splice donor site and leading to a truncated protein. This is the second report of LCA5 mutations causing LCA. It may also be significant that one affected child died at eleven months of age due to asphyxia during sleep. To date the only phenotype unambiguously associated with mutations in this gene is LCA. However the LCA5 gene is known to be expressed in nasopharynx, trachea and lungs and was originally identified in the proteome of bronchial epithelium ciliary axonemes. The cause of death in this child may therefore imply that LCA5 mutations can in fact cause a wider spectrum of phenotypes including respiratory disease.

Dataset Information

A Novel Splice-Site Mutation in the ELN Gene Suggests an Alternative Mechanism for Vascular Elastinopathies.

Publications

A Novel Splice-Site Mutation in the <i>ELN</i> Gene Suggests an Alternative Mechanism for Vascular Elastinopathies.

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