A novel splicing mutation in the ABCA1 gene, causing Tangier disease and familial HDL deficiency in a large family
| Autor: | Anna Montali, Pietro Gallo, Marianna Maranghi, Antonio Gallo, Francesco Alesini, Marco Lucarelli, Marcello Arca, Antonella Verrienti, Elvira Grieco, Gessica Truglio |
|---|---|
| Přispěvatelé: | Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Department of Cellular Biotechnologies and Haematology, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Heterozygote Truncated proteins Intronic mutations RNA Splicing Biophysics Tangier disease Gene mutation Biology Compound heterozygosity medicine.disease_cause Biochemistry 03 medical and health sciences Exon 0302 clinical medicine ABCA1 gene medicine Humans Family Molecular Biology Familial HDL deficiency Splicing defects ATP Binding Cassette Transporter 1 Hypoalphalipoproteinemias Genetics Mutation Intron nutritional and metabolic diseases [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology Cell Biology [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism medicine.disease Stop codon Introns 3. Good health Pedigree 030104 developmental biology [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics Codon Nonsense 030220 oncology & carcinogenesis ABCA1 biology.protein Female lipids (amino acids peptides and proteins) RNA Splice Sites |
| Zdroj: | Biochemical and Biophysical Research Communications Biochemical and Biophysical Research Communications, Elsevier, 2019, 508 (2), pp.487-493. ⟨10.1016/j.bbrc.2018.11.064⟩ |
| ISSN: | 0006-291X 1090-2104 |
| DOI: | 10.1016/j.bbrc.2018.11.064⟩ |
| Popis: | International audience; Tangier disease is a rare disorder of lipoprotein metabolism that presents with extremely low levels of HDL cholesterol and apoprotein A-I. It is caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene. Clinical heterogeneity and mutational pattern of Tangier disease are poorly characterized. Moreover, also familial HDL deficiency may be caused by mutations in ABCA1 gene. ATP-binding cassette transporter A1 (ABCA1) gene mutations in a patient with Tangier disease, who presented an uncommon clinical history, and in his family were found and characterized. He was found to be compound heterozygous for two intronic mutations of ABCA1 gene, causing abnormal pre-mRNAs splicing. The novel c.1510-1G > A mutation was located in intron 12 and caused the activation of a cryptic splice site in exon 13, which determined the loss of 22 amino acids of exon 13 with the introduction of a premature stop codon. Five heterozygous carriers of this mutation were also found in proband's family, all presenting reduced HDL cholesterol and ApoAI (0.86 ± 0.16 mmol/L and 92.2 ± 10.9 mg/dL respectively), but not the typical features of Tangier disease, a phenotype compatible with the diagnosis of familial HDL deficiency. The other known mutation c.1195-27G > A was confirmed to cause aberrant retention of 25 nucleotides of intron 10 leading to the insertion of a stop codon after 20 amino acids of exon 11. Heterozygous carriers of this mutation also showed the clinical phenotype of familial HDL deficiency. Our study extends the catalog of pathogenic intronic mutations affecting ABCA1 pre-mRNA splicing. In a large family, a clear demonstration that the same mutations may cause Tangier disease (if in compound heterozygosis) or familial HDL deficiency (if in heterozygosis) is provided. |
| Databáze: | OpenAIRE |
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