A novel splice site mutation of the LDL receptor gene in a Tunisian hypercholesterolemic family

Jelassi, Awatef; Najah, Mohamed; Jguirim, Imen; Maatouk, Fethi; Lestavel, Sophie; Laroussi, O.S.; Rouis, Mustapha; Boileau, Cathérine; Rabès, Jean-Pierre; Varret, Mathilde; Slimane, Mohamed Naceur

doi:10.1016/j.cca.2008.02.019

Cited by 16 publications

(10 citation statements)

References 23 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%

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%

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 majority of mutations identified in the LDLR gene are point mutations (5). However, this figure could be an underestimate as screening programmes have tended to focus on screening for point mutations by methods such as single-strand conformation polymorphism (SSCP) analysis (7), denaturing high-performance liquid chromatography (dHPLC) electrophoresis (8), and more recently by direct sequence analysis (9). However, this figure could be an underestimate as screening programmes have tended to focus on screening for point mutations by methods such as single-strand conformation polymorphism (SSCP) analysis (7), denaturing high-performance liquid chromatography (dHPLC) electrophoresis (8), and more recently by direct sequence analysis (9).…”

mentioning

confidence: 99%

Multiplex ligation‐dependent probe amplification analysis to screen for deletions and duplications of the LDLR gene in patients with familial hypercholesterolaemia

et al. 2009

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The most common genetic defect in patients with autosomal dominant hypercholesterolaemia is a mutation of the low-density lipoprotein receptor (LDLR) gene. An estimate of the frequency of major rearrangements has been limited by the availability of an effective analytical method and testing of large cohorts. We present data from a cohort of 611 patients referred with suspected heterozygous familial hypercholesterolaemia (FH) from five UK lipid clinics, who were initially screened for point mutations in LDLR and the common APOB and PCSK9 mutations. The 377 cases in whom no mutation was found were then screened for large rearrangements by multiplex ligation-dependent probe amplification (MLPA) analysis. A rearrangement was identified in 19 patients. This represents 7.5% of the total detected mutations of the cohort. Of these, the majority of mutations (12/19) were deletions of more than one exon, two were duplications of more than one exon and five were single exon deletions that need interpreting with care. Five rearrangements (26%) are previously unreported. We conclude that MLPA analysis is a simple and rapid method for detecting large rearrangements and should be included in diagnostic genetic testing for FH.

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“…The frequency of intronic variants being reported is increasing as the regions of the gene being screened now include more of the intronic sequences [14]. Any sequence changes that disrupt the canonical exon-intron consensus splice sequences (as was recently reported for a sequence change 1 bp into intron 8 found in a patient from Tunisia [15]) can be safely predicted to affect normal splicing; 67% of the 87 intronic variants reported fall into this category. A clinical diagnostic laboratory would normally accept such changes as being pathogenic but would require further evidence for changes more than 5 bp from the consensus sites [7 ].…”

Section: Determining the Functionality Of Intronic Variantsmentioning

confidence: 93%

What is the clinical utility of DNA testing in patients with familial hypercholesterolaemia?

Humphries

Norbury

Leigh

et al. 2008

Current Opinion in Lipidology

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DNA testing, as an adjunct to the measurement of plasma low-density lipoprotein cholesterol levels, has clinical utility in providing an unequivocal diagnosis in patients and in identifying affected relatives at an early age so that they can be offered lifestyle advice and appropriate lipid-lowering therapies. Researchers and DNA diagnostic laboratories need to interpret novel sequence changes with caution in order to avoid a false positive diagnosis.

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A novel splice site mutation of the LDL receptor gene in a Tunisian hypercholesterolemic family

Cited by 16 publications

References 23 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

Multiplex ligation‐dependent probe amplification analysis to screen for deletions and duplications of the LDLR gene in patients with familial hypercholesterolaemia

What is the clinical utility of DNA testing in patients with familial hypercholesterolaemia?

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