Exploiting in silico structural analysis to introduce emerging genotype–phenotype correlations in DHCR24-related sterol biosynthesis disorder: a case study
Desmosterolosis is a rare sterol biosynthesis disorder characterized by multiple congenital anomalies, failure to thrive, severe developmental delay, progressive epileptic encephalopathy, and elevated levels of desmosterol caused by biallelic mutations of DHCR24 encoding 3-β-hydroxysterol Δ-24-reduc...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2023.1307934/full |
| _version_ | 1797366168034476032 |
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| author | Dario Cocciadiferro Tommaso Mazza Davide Vecchio Tommaso Biagini Francesco Petrizzelli Emanuele Agolini Andrea Villani Andrea Villani Daniele Minervino Diego Martinelli Cristiano Rizzo Sara Boenzi Filippo Maria Panfili Paola Sabrina Buonuomo Marina Macchiaiolo Andrea Bartuli Antonio Novelli |
| author_facet | Dario Cocciadiferro Tommaso Mazza Davide Vecchio Tommaso Biagini Francesco Petrizzelli Emanuele Agolini Andrea Villani Andrea Villani Daniele Minervino Diego Martinelli Cristiano Rizzo Sara Boenzi Filippo Maria Panfili Paola Sabrina Buonuomo Marina Macchiaiolo Andrea Bartuli Antonio Novelli |
| author_sort | Dario Cocciadiferro |
| collection | DOAJ |
| description | Desmosterolosis is a rare sterol biosynthesis disorder characterized by multiple congenital anomalies, failure to thrive, severe developmental delay, progressive epileptic encephalopathy, and elevated levels of desmosterol caused by biallelic mutations of DHCR24 encoding 3-β-hydroxysterol Δ-24-reductase. DHCR24 is regarded as the key enzyme of cholesterol synthesis in the metabolism of brain cholesterol as it catalyzes the reduction of the Δ-24 double bond of sterol intermediates during cholesterol biosynthesis. To date, 15 DHCR24 variants, detected in 2 related and 14 unrelated patients, have been associated with the desmosterolosis disorder. Here, we describe a proband harboring the never-described DHCR24 homozygous missense variant NM_014762.4:c.506T>C, NP_055577.1:p.M169T, whose functional validation was confirmed through biochemical assay. By using molecular dynamics simulation techniques, we investigated the impact of this variant on the protein stability and interaction network with the flavin adenine dinucleotide cofactor, thereby providing a preliminary assessment of its mechanistic role in comparison to all known pathogenic variants, the wild-type protein, and a known benign DHCR24 variant. This report expands the clinical and molecular spectra of the DHCR24-related disorder, reports on a novel DHCR24 deleterious variant associated with desmosterolosis, and gives new insights into genotype–phenotype correlations. |
| first_indexed | 2024-03-08T17:01:27Z |
| format | Article |
| id | doaj.art-eddb7ff654c54ace841f99d9db7f610d |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-03-08T17:01:27Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-eddb7ff654c54ace841f99d9db7f610d2024-01-04T14:17:02ZengFrontiers Media S.A.Frontiers in Genetics1664-80212024-01-011410.3389/fgene.2023.13079341307934Exploiting in silico structural analysis to introduce emerging genotype–phenotype correlations in DHCR24-related sterol biosynthesis disorder: a case studyDario Cocciadiferro0Tommaso Mazza1Davide Vecchio2Tommaso Biagini3Francesco Petrizzelli4Emanuele Agolini5Andrea Villani6Andrea Villani7Daniele Minervino8Diego Martinelli9Cristiano Rizzo10Sara Boenzi11Filippo Maria Panfili12Paola Sabrina Buonuomo13Marina Macchiaiolo14Andrea Bartuli15Antonio Novelli16Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyBioinformatics Unit, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, ItalyRare Diseases and Medical Genetics Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyBioinformatics Unit, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, ItalyBioinformatics Unit, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, ItalyTranslational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyTranslational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyBioinformatics Unit, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, ItalyTranslational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyDivision of Metabolic Diseases, Bambino Gesù Children’s Hospital IRCCS, Rome, ItalyDivision of Metabolic Diseases, Bambino Gesù Children’s Hospital IRCCS, Rome, ItalyDivision of Metabolic Diseases, Bambino Gesù Children’s Hospital IRCCS, Rome, ItalyRare Diseases and Medical Genetics Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyRare Diseases and Medical Genetics Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyRare Diseases and Medical Genetics Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyRare Diseases and Medical Genetics Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyTranslational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, ItalyDesmosterolosis is a rare sterol biosynthesis disorder characterized by multiple congenital anomalies, failure to thrive, severe developmental delay, progressive epileptic encephalopathy, and elevated levels of desmosterol caused by biallelic mutations of DHCR24 encoding 3-β-hydroxysterol Δ-24-reductase. DHCR24 is regarded as the key enzyme of cholesterol synthesis in the metabolism of brain cholesterol as it catalyzes the reduction of the Δ-24 double bond of sterol intermediates during cholesterol biosynthesis. To date, 15 DHCR24 variants, detected in 2 related and 14 unrelated patients, have been associated with the desmosterolosis disorder. Here, we describe a proband harboring the never-described DHCR24 homozygous missense variant NM_014762.4:c.506T>C, NP_055577.1:p.M169T, whose functional validation was confirmed through biochemical assay. By using molecular dynamics simulation techniques, we investigated the impact of this variant on the protein stability and interaction network with the flavin adenine dinucleotide cofactor, thereby providing a preliminary assessment of its mechanistic role in comparison to all known pathogenic variants, the wild-type protein, and a known benign DHCR24 variant. This report expands the clinical and molecular spectra of the DHCR24-related disorder, reports on a novel DHCR24 deleterious variant associated with desmosterolosis, and gives new insights into genotype–phenotype correlations.https://www.frontiersin.org/articles/10.3389/fgene.2023.1307934/fullDHCR24desmosterolosisgenotype–phenotype correlationstructural biologymedical geneticsbioinformatics |
| spellingShingle | Dario Cocciadiferro Tommaso Mazza Davide Vecchio Tommaso Biagini Francesco Petrizzelli Emanuele Agolini Andrea Villani Andrea Villani Daniele Minervino Diego Martinelli Cristiano Rizzo Sara Boenzi Filippo Maria Panfili Paola Sabrina Buonuomo Marina Macchiaiolo Andrea Bartuli Antonio Novelli Exploiting in silico structural analysis to introduce emerging genotype–phenotype correlations in DHCR24-related sterol biosynthesis disorder: a case study Frontiers in Genetics DHCR24 desmosterolosis genotype–phenotype correlation structural biology medical genetics bioinformatics |
| title | Exploiting in silico structural analysis to introduce emerging genotype–phenotype correlations in DHCR24-related sterol biosynthesis disorder: a case study |
| title_full | Exploiting in silico structural analysis to introduce emerging genotype–phenotype correlations in DHCR24-related sterol biosynthesis disorder: a case study |
| title_fullStr | Exploiting in silico structural analysis to introduce emerging genotype–phenotype correlations in DHCR24-related sterol biosynthesis disorder: a case study |
| title_full_unstemmed | Exploiting in silico structural analysis to introduce emerging genotype–phenotype correlations in DHCR24-related sterol biosynthesis disorder: a case study |
| title_short | Exploiting in silico structural analysis to introduce emerging genotype–phenotype correlations in DHCR24-related sterol biosynthesis disorder: a case study |
| title_sort | exploiting in silico structural analysis to introduce emerging genotype phenotype correlations in dhcr24 related sterol biosynthesis disorder a case study |
| topic | DHCR24 desmosterolosis genotype–phenotype correlation structural biology medical genetics bioinformatics |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2023.1307934/full |
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