Identifying and predicting the pathogenic effects of a novel variant inducing severe early onset MMA: a bioinformatics approach
Abstract Background Methylmalonic acidemia (MMA) is a rare metabolic disorder resulting from functional defects in methylmalonyl-CoA mutase. Mutations in the MMAB gene are responsible for the cblB type of vitamin B12-responsive MMA. Results This study used Whole-exome sequencing (WES), Sanger sequen...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-05-01
|
| Series: | Hereditas |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s41065-023-00281-0 |
| _version_ | 1797811454089363456 |
|---|---|
| author | Fereshteh Maryami Elham Rismani Elham Davoudi-Dehaghani Nasrin Khalesi Fatemeh Zafarghandi Motlagh Alireza Kordafshari Saeed Talebi Hamzeh Rahimi Sirous Zeinali |
| author_facet | Fereshteh Maryami Elham Rismani Elham Davoudi-Dehaghani Nasrin Khalesi Fatemeh Zafarghandi Motlagh Alireza Kordafshari Saeed Talebi Hamzeh Rahimi Sirous Zeinali |
| author_sort | Fereshteh Maryami |
| collection | DOAJ |
| description | Abstract Background Methylmalonic acidemia (MMA) is a rare metabolic disorder resulting from functional defects in methylmalonyl-CoA mutase. Mutations in the MMAB gene are responsible for the cblB type of vitamin B12-responsive MMA. Results This study used Whole-exome sequencing (WES), Sanger sequencing, linkage analysis, and in-silico evaluation of the variants’ effect on protein structure and function to confirm their pathogenicity in a 2-day-old neonate presenting an early-onset metabolic crisis and death. WES revealed a homozygous missense variant on chromosome 12, the NM_052845.4 (MMAB):c.557G > A, p.Arg186Gln, in exon 7, a highly conserved and hot spot region for pathogenic variants. After being confirmed by Sanger sequencing, the wild-type and mutant proteins’ structure and function were modeled and examined using in-silico bioinformatics tools and compared to the variant NM_052845.4 (MMAB):c.556C > T, p.Arg186Trp, a known pathogenic variant at the same position. Comprehensive bioinformatics analysis showed a significant reduction in the stability of variants and changes in protein–protein and ligand–protein interactions. Interestingly, the variant c.557G > A, p.Arg186Gln depicted more variations in the secondary structure and less binding to the ATP and B12 ligands compared to the c.556C > T, p.Arg186Trp, the known pathogenic variant. Conclusion This study succeeded in expanding the variant spectra of the MMAB, forasmuch as the variant c.557G > A, p.Arg186Gln is suggested as a pathogenic variant and the cause of severe MMA and neonatal death. These results benefit the prenatal diagnosis of MMA in the subsequent pregnancies and carrier screening of the family members. Furthermore, as an auxiliary technique, homology modeling and protein structure and function evaluations could provide geneticists with a more accurate interpretation of variants’ pathogenicity. Graphical Abstract |
| first_indexed | 2024-03-13T07:23:16Z |
| format | Article |
| id | doaj.art-70d8c593cda74a6cbeb5034735dc8991 |
| institution | Directory Open Access Journal |
| issn | 1601-5223 |
| language | English |
| last_indexed | 2024-03-13T07:23:16Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Hereditas |
| spelling | doaj.art-70d8c593cda74a6cbeb5034735dc89912023-06-04T11:30:43ZengBMCHereditas1601-52232023-05-01160111610.1186/s41065-023-00281-0Identifying and predicting the pathogenic effects of a novel variant inducing severe early onset MMA: a bioinformatics approachFereshteh Maryami0Elham Rismani1Elham Davoudi-Dehaghani2Nasrin Khalesi3Fatemeh Zafarghandi Motlagh4Alireza Kordafshari5Saeed Talebi6Hamzeh Rahimi7Sirous Zeinali8Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of IranDepartment of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of IranDepartment of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of IranDepartment of Pediatrics and Neonatal Intensive Care Unit, Ali-Asghar Children’s Hospital, Iran University of Medical SciencesMedical Genetics Lab, Kawsar Human Genetics Research CenterDepartment of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of IranDepartment of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences (IUMS)Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of IranDepartment of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of IranAbstract Background Methylmalonic acidemia (MMA) is a rare metabolic disorder resulting from functional defects in methylmalonyl-CoA mutase. Mutations in the MMAB gene are responsible for the cblB type of vitamin B12-responsive MMA. Results This study used Whole-exome sequencing (WES), Sanger sequencing, linkage analysis, and in-silico evaluation of the variants’ effect on protein structure and function to confirm their pathogenicity in a 2-day-old neonate presenting an early-onset metabolic crisis and death. WES revealed a homozygous missense variant on chromosome 12, the NM_052845.4 (MMAB):c.557G > A, p.Arg186Gln, in exon 7, a highly conserved and hot spot region for pathogenic variants. After being confirmed by Sanger sequencing, the wild-type and mutant proteins’ structure and function were modeled and examined using in-silico bioinformatics tools and compared to the variant NM_052845.4 (MMAB):c.556C > T, p.Arg186Trp, a known pathogenic variant at the same position. Comprehensive bioinformatics analysis showed a significant reduction in the stability of variants and changes in protein–protein and ligand–protein interactions. Interestingly, the variant c.557G > A, p.Arg186Gln depicted more variations in the secondary structure and less binding to the ATP and B12 ligands compared to the c.556C > T, p.Arg186Trp, the known pathogenic variant. Conclusion This study succeeded in expanding the variant spectra of the MMAB, forasmuch as the variant c.557G > A, p.Arg186Gln is suggested as a pathogenic variant and the cause of severe MMA and neonatal death. These results benefit the prenatal diagnosis of MMA in the subsequent pregnancies and carrier screening of the family members. Furthermore, as an auxiliary technique, homology modeling and protein structure and function evaluations could provide geneticists with a more accurate interpretation of variants’ pathogenicity. Graphical Abstracthttps://doi.org/10.1186/s41065-023-00281-0Methylmalonic acidemiaWhole-exome sequencingMMABCorrinoid adenosyltransferaseHomology modelingBioinformatics |
| spellingShingle | Fereshteh Maryami Elham Rismani Elham Davoudi-Dehaghani Nasrin Khalesi Fatemeh Zafarghandi Motlagh Alireza Kordafshari Saeed Talebi Hamzeh Rahimi Sirous Zeinali Identifying and predicting the pathogenic effects of a novel variant inducing severe early onset MMA: a bioinformatics approach Hereditas Methylmalonic acidemia Whole-exome sequencing MMAB Corrinoid adenosyltransferase Homology modeling Bioinformatics |
| title | Identifying and predicting the pathogenic effects of a novel variant inducing severe early onset MMA: a bioinformatics approach |
| title_full | Identifying and predicting the pathogenic effects of a novel variant inducing severe early onset MMA: a bioinformatics approach |
| title_fullStr | Identifying and predicting the pathogenic effects of a novel variant inducing severe early onset MMA: a bioinformatics approach |
| title_full_unstemmed | Identifying and predicting the pathogenic effects of a novel variant inducing severe early onset MMA: a bioinformatics approach |
| title_short | Identifying and predicting the pathogenic effects of a novel variant inducing severe early onset MMA: a bioinformatics approach |
| title_sort | identifying and predicting the pathogenic effects of a novel variant inducing severe early onset mma a bioinformatics approach |
| topic | Methylmalonic acidemia Whole-exome sequencing MMAB Corrinoid adenosyltransferase Homology modeling Bioinformatics |
| url | https://doi.org/10.1186/s41065-023-00281-0 |
| work_keys_str_mv | AT fereshtehmaryami identifyingandpredictingthepathogeniceffectsofanovelvariantinducingsevereearlyonsetmmaabioinformaticsapproach AT elhamrismani identifyingandpredictingthepathogeniceffectsofanovelvariantinducingsevereearlyonsetmmaabioinformaticsapproach AT elhamdavoudidehaghani identifyingandpredictingthepathogeniceffectsofanovelvariantinducingsevereearlyonsetmmaabioinformaticsapproach AT nasrinkhalesi identifyingandpredictingthepathogeniceffectsofanovelvariantinducingsevereearlyonsetmmaabioinformaticsapproach AT fatemehzafarghandimotlagh identifyingandpredictingthepathogeniceffectsofanovelvariantinducingsevereearlyonsetmmaabioinformaticsapproach AT alirezakordafshari identifyingandpredictingthepathogeniceffectsofanovelvariantinducingsevereearlyonsetmmaabioinformaticsapproach AT saeedtalebi identifyingandpredictingthepathogeniceffectsofanovelvariantinducingsevereearlyonsetmmaabioinformaticsapproach AT hamzehrahimi identifyingandpredictingthepathogeniceffectsofanovelvariantinducingsevereearlyonsetmmaabioinformaticsapproach AT sirouszeinali identifyingandpredictingthepathogeniceffectsofanovelvariantinducingsevereearlyonsetmmaabioinformaticsapproach |