Silent exonic mutations in the low‐density lipoprotein receptor gene that cause familial hypercholesterolemia by affecting mRNA splicing

Defesche, Joep C.; Schuurman, E.J.M.; Klaaijsen, Lisette N.; Khoo, K.L.; Wiegman, Albert; Stalenhoef, Anton F. H.

doi:10.1111/j.1399-0004.2008.00999.x

Cited by 27 publications

(18 citation statements)

References 19 publications

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“…Many different human diseases can be caused by errors in mRNA splicing or its regulation. Interestingly, intronic deletions causing exon skipping or intron retention in the human LDLR gene were identified in patients with familial hypercholesterolemia (4,9,12,22,40). Because the human LDLR gene is homologous to the chicken tva gene, it is tempting to speculate that this is a common mechanism of mutagenesis within this gene family.…”

Section: Discussionmentioning

confidence: 99%

“…The same intronic deletions were also found in a subspecies of red jungle fowl, Gallus gallus murghi. The frequent disrup-tion of splicing signals resembles the situation in the low-density lipoprotein receptor gene, a human homologue of chicken tva, in patients with familial hypercholesterolemia (12,40). We conclude that ASLV receptor alleles determining the decreased sensitivity to avian retroviruses are common in the population of domestic chick as well as in wildfowl and could play an important role in virus-host coevolution.…”

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confidence: 87%

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Intronic Deletions That Disrupt mRNA Splicing of the tva Receptor Gene Result in Decreased Susceptibility to Infection by Avian Sarcoma and Leukosis Virus Subgroup A

Reinišová

Plachý

Trejbalová

et al. 2012

J Virol

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The group of closely related avian sarcoma and leukosis viruses (ASLVs) evolved from a common ancestor into multiple subgroups, A to J, with differential host range among galliform species and chicken lines. These subgroups differ in variable parts of their envelope glycoproteins, the major determinants of virus interaction with specific receptor molecules. Three genetic loci, tva, tvb, and tvc, code for single membrane-spanning receptors from diverse protein families that confer susceptibility to the ASLV subgroups. The host range expansion of the ancestral virus might have been driven by gradual evolution of resistance in host cells, and the resistance alleles in all three receptor loci have been identified. Here, we characterized two alleles of the tva receptor gene with similar intronic deletions comprising the deduced branch-point signal within the first intron and leading to inefficient splicing of tva mRNA. As a result, we observed decreased susceptibility to subgroup A ASLV in vitro and in vivo. These alleles were independently found in a close-bred line of domestic chicken and Indian red jungle fowl (Gallus gallus murghi), suggesting that their prevalence might be much wider in outbred chicken breeds. We identified defective splicing to be a mechanism of resistance to ASLV and conclude that such a type of mutation could play an important role in virus-host coevolution. Retroviruses enter the host cell through specific receptors, cell surface proteins with high affinity to viral envelope glycoproteins. The interaction between receptors and viral glycoproteins is very complex and includes the initial attachment of the virion, profound conformational changes in the structure of the viral glycoprotein, exposure of fusion peptides, and, ultimately, the fusion of viral and cellular membranes (5, 47). Despite the strict structural requirements for these interactions, hypervariability of retroviral glycoproteins can change the receptor usage and broaden the host range. Indeed, closely related families of retroviruses have evolved into multiple subgroups that utilize different cellular surface proteins as receptors. For example, the group of avian alpharetroviruses avian sarcoma and leukosis viruses (ASLVs) comprise 10 related subgroups, A to J, which either do not interfere at all with each other or interfere only nonreciprocally in infecting chicken cells. The susceptibility of chicken cells to highly related ASLV subgroups A to E is determined by three genetic loci, tva, tvb, and tvc (5, 41). The Tva protein belongs to the family of low-density lipoprotein receptors (LDLRs) (6, 48) and determines susceptibility to the subgroup A ASLVs. The tumor necrosis factor receptor-related protein Tvb confers susceptibility to subgroup B, D, and E ASLVs by three nonoverlapping binding sites (2,3,8), and the Tvc protein, closely related to the mammalian butyrophilins, serves as receptor for C subgroup ASLV (14).The rapid evolution of novel retrovirus envelopes is compelled by the appearance of host entry restrictions. Gen...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 87%

Intronic Deletions That Disrupt mRNA Splicing of the tva Receptor Gene Result in Decreased Susceptibility to Infection by Avian Sarcoma and Leukosis Virus Subgroup A

Reinišová

Plachý

Trejbalová

et al. 2012

J Virol

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“…Analysis of mRNA from the patient's cells showed that the mutation introduces a new splice site, which is used to the exclusion of the natural splice site and causes a deletion of 31 bp from the mRNA, predicted to introduce premature termination four codons after Arg406 (p.Ser397Thrfs Ã 6). In 2008, a Dutch group published another synonymous variant, c.621C>G, p.(Gly207Gly), as cause of splicing defect [50]. A novel synonymous variant c.1813C>T, p.(Leu605-Leu) has been recently characterized as having an effect on splicing [51 & ], introducing also a premature stop codon.…”

Section: Putative Splicing Variantsmentioning

confidence: 99%

Low-density lipoprotein receptor mutational analysis in diagnosis of familial hypercholesterolemia

Bourbon

Alves

Sijbrands

2017

Current Opinion in Lipidology

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Purpose of reviewTo present up to date evidence on the pathogenicity of low-density lipoprotein receptor (LDLR) variants and to propose a strategy that is suitable for implementation in the clinical work-up of familial hypercholesterolaemia. Recent findingsMore than 1800 variants have been described in the LDLR gene of patients with a clinical diagnosis of familial hypercholesterolaemia; however, less than 15% have functional evidence of pathogenicity. SummaryThe spectrum of variants in the LDLR identified in patients with clinical familial hypercholesterolaemia is increasing as novel variants are still being reported. However, over 50% of all LDLR variants need further evidence before they can be confirmed as mutations causing disease. Even with applying the recent American College of Medical Genetics variant classification, a large number of variants are still considered variants of unknown significance. Before obtaining an undisputable confirmation of the effect on the expression and activity of the LDLR, reporting these variants as part of a clinical diagnosis to the patient holds the risk that it might need to be withdrawn in a later stage. An investment should be made to develop functional assays to characterize LDLR variants of unknown significance for a better patient diagnosis and to prevent confusion in the physician's office.

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“…Five variants, c.1246AϾC, c.1448CϾT, c.1740GϾA, c.2130CϾT, and c.2229AϾG, are silent mutations. However, a potential effect on gene splicing [37][38][39] or on protein function 40 cannot be ruled out. Seven homozygous variants were also included in the HRM variant panel.…”

Section: Hrm Analysis Of Patient Samples With Variants Detected In Thmentioning

confidence: 99%

Mutation Analysis of SLC26A4 for Pendred Syndrome and Nonsyndromic Hearing Loss by High-Resolution Melting

Chen

Tranebjærg

Rendtorff

et al. 2011

The Journal of Molecular Diagnostics

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Pendred syndrome and DFNB4 (autosomal recessive nonsyndromic congenital deafness, locus 4) are associated with autosomal recessive congenital sensorineural hearing loss and mutations in the SLC26A4 gene. Extensive allelic heterogeneity, however, necessitates analysis of all exons and splice sites to identify mutations for individual patients. Although Sanger sequencing is the gold standard for mutation detection, screening methods supplemented with targeted sequencing can provide a cost-effective alternative. One such method, denaturing high-performance liquid chromatography, was developed for clinical mutation detection in SLC26A4. However, this method inherently cannot distinguish homozygous changes from wild-type sequences. High-resolution melting (HRM), on the other hand, can detect heterozygous and homozygous changes cost-effectively, without any post-PCR modifications. We developed a closed-tube HRM mutation detection method specific for SLC26A4 that can be used in the clinical diagnostic setting. Twenty-eight primer pairs were designed to cover all 21 SLC26A4 exons and splice junction sequences. Using the resulting amplicons, initial HRM analysis detected all 45 variants previously identified by sequencing. Subsequently, a 384-well plate format was designed for up to three patient samples per run. Blinded HRM testing on these plates of patient samples collected over 1 year in a clinical diagnostic laboratory accurately detected all variants identified by sequencing. In conclusion, HRM with targeted sequencing is a reliable, simple, and cost-effective method for SLC26A4 mutation screening and detection. Pendred syndrome and DFNB4 (autosomal recessive nonsyndromic congenital deafness, locus 4) are associated with autosomal recessive congenital sensorineural hearing loss. Whereas Pendred syndrome is thought to be the most common cause of syndromic hearing loss, 1,2 DFNB4 is a nonsyndromic form of hearing loss caused by mutations in the same gene. 3 Clinically, both can be associated with temporal bone abnormalities. 4 In addition, an abnormal perchlorate discharge test result and/or euthyroid goiter can be present in patients with Pendred syndrome but not in those with DFNB4. 3,4 This may be due to allelic heterogeneity because differences in residual activity of the protein products render different phenotypes. 5

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Silent exonic mutations in the low‐density lipoprotein receptor gene that cause familial hypercholesterolemia by affecting mRNA splicing

Cited by 27 publications

References 19 publications

Intronic Deletions That Disrupt mRNA Splicing of the tva Receptor Gene Result in Decreased Susceptibility to Infection by Avian Sarcoma and Leukosis Virus Subgroup A

Intronic Deletions That Disrupt mRNA Splicing of the tva Receptor Gene Result in Decreased Susceptibility to Infection by Avian Sarcoma and Leukosis Virus Subgroup A

Low-density lipoprotein receptor mutational analysis in diagnosis of familial hypercholesterolemia

Mutation Analysis of SLC26A4 for Pendred Syndrome and Nonsyndromic Hearing Loss by High-Resolution Melting

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