An attenuated, adult case of AADC deficiency demonstrated by protein characterization
A case of an adult with borderline AADC deficiency symptoms is presented here. Genetic analysis revealed that the patient carries two AADC variants (NM_000790.3: c.1040G > A and c.679G > C) in compound heterozygosis, resulting in p.Arg347Gln and p.Glu227Gln amino acid alterations. While p.Arg3...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-06-01
|
| Series: | Molecular Genetics and Metabolism Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426924000247 |
| _version_ | 1797259973995003904 |
|---|---|
| author | Giovanni Bisello Christiaan G.J. Saris Rossella Franchini Marcel M. Verbeek Michel A.A.P. Willemsen Massimiliano Perduca Mariarita Bertoldi |
| author_facet | Giovanni Bisello Christiaan G.J. Saris Rossella Franchini Marcel M. Verbeek Michel A.A.P. Willemsen Massimiliano Perduca Mariarita Bertoldi |
| author_sort | Giovanni Bisello |
| collection | DOAJ |
| description | A case of an adult with borderline AADC deficiency symptoms is presented here. Genetic analysis revealed that the patient carries two AADC variants (NM_000790.3: c.1040G > A and c.679G > C) in compound heterozygosis, resulting in p.Arg347Gln and p.Glu227Gln amino acid alterations. While p.Arg347Gln is a known pathogenic variant, p.Glu227Gln is unknown. Combining clinical features to bioinformatic and molecular characterization of the AADC protein population of the patient (p.Arg347Gln/p.Arg347Gln homodimer, p.Glu227Gln/p.Glu227Gln homodimer, and p.Glu227Gln/p.Arg347Gln heterodimer), we determined that: i) the p.Arg347Gln/p.Arg347Gln homodimer is inactive since the alteration affects a catalytically essential structural element at the active site, ii) the p.Glu227Gln/p.Glu227Gln homodimer is as active as the wild-type AADC since the alteration occurs at the surface and does not change the chemical nature of the amino acid, and iii) the p.Glu227Gln/p.Arg347Gln heterodimer has a catalytic efficiency 75% that of the wild-type since only one of the two active sites is compromised, thus demonstrating a positive complementation. By this approach, the molecular basis for the mild presentation of the disease is provided, and the experience made can also be useful for personalized therapeutic decisions in other mild AADC deficiency patients. Interestingly, in the last few years, many previously undiagnosed or misdiagnosed patients have been identified as mild cases of AADC deficiency, expanding the phenotype of this neurotransmitter disease. |
| first_indexed | 2024-04-24T23:17:57Z |
| format | Article |
| id | doaj.art-f88bb0ba303b4684a3d20c32400d0a85 |
| institution | Directory Open Access Journal |
| issn | 2214-4269 |
| language | English |
| last_indexed | 2024-04-24T23:17:57Z |
| publishDate | 2024-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Genetics and Metabolism Reports |
| spelling | doaj.art-f88bb0ba303b4684a3d20c32400d0a852024-03-17T07:53:58ZengElsevierMolecular Genetics and Metabolism Reports2214-42692024-06-0139101071An attenuated, adult case of AADC deficiency demonstrated by protein characterizationGiovanni Bisello0Christiaan G.J. Saris1Rossella Franchini2Marcel M. Verbeek3Michel A.A.P. Willemsen4Massimiliano Perduca5Mariarita Bertoldi6Department of Neuroscience, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Strada Le Grazie 8, 37134 Verona, ItalyDepartment of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Geert Grooteplein 10, 6525 GA Nijmegen, the NetherlandsDepartment of Neuroscience, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Strada Le Grazie 8, 37134 Verona, ItalyDepartment of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands; Translational Metabolic Laboratory, Department of Human Gentics, Radboud University Medical Centre, Geert Grooteplein 10, 6525 GA Nijmegen, the NetherlandsDepartment of Pediatric Neurology, Radboud University Medical Centre, Geert Grooteplein 10, 6525 GA Nijmegen, the NetherlandsDepartment of Biotechnology, University of Verona, Strada Le Grazie 15, 37134 Verona, ItalyDepartment of Neuroscience, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy; Corresponding author.A case of an adult with borderline AADC deficiency symptoms is presented here. Genetic analysis revealed that the patient carries two AADC variants (NM_000790.3: c.1040G > A and c.679G > C) in compound heterozygosis, resulting in p.Arg347Gln and p.Glu227Gln amino acid alterations. While p.Arg347Gln is a known pathogenic variant, p.Glu227Gln is unknown. Combining clinical features to bioinformatic and molecular characterization of the AADC protein population of the patient (p.Arg347Gln/p.Arg347Gln homodimer, p.Glu227Gln/p.Glu227Gln homodimer, and p.Glu227Gln/p.Arg347Gln heterodimer), we determined that: i) the p.Arg347Gln/p.Arg347Gln homodimer is inactive since the alteration affects a catalytically essential structural element at the active site, ii) the p.Glu227Gln/p.Glu227Gln homodimer is as active as the wild-type AADC since the alteration occurs at the surface and does not change the chemical nature of the amino acid, and iii) the p.Glu227Gln/p.Arg347Gln heterodimer has a catalytic efficiency 75% that of the wild-type since only one of the two active sites is compromised, thus demonstrating a positive complementation. By this approach, the molecular basis for the mild presentation of the disease is provided, and the experience made can also be useful for personalized therapeutic decisions in other mild AADC deficiency patients. Interestingly, in the last few years, many previously undiagnosed or misdiagnosed patients have been identified as mild cases of AADC deficiency, expanding the phenotype of this neurotransmitter disease.http://www.sciencedirect.com/science/article/pii/S2214426924000247Aromatic amino acid decarboxylaseAADC deficiencyPyridoxal 5′-phosphateCompound heterozygosisGenotype-phenotype correlation |
| spellingShingle | Giovanni Bisello Christiaan G.J. Saris Rossella Franchini Marcel M. Verbeek Michel A.A.P. Willemsen Massimiliano Perduca Mariarita Bertoldi An attenuated, adult case of AADC deficiency demonstrated by protein characterization Molecular Genetics and Metabolism Reports Aromatic amino acid decarboxylase AADC deficiency Pyridoxal 5′-phosphate Compound heterozygosis Genotype-phenotype correlation |
| title | An attenuated, adult case of AADC deficiency demonstrated by protein characterization |
| title_full | An attenuated, adult case of AADC deficiency demonstrated by protein characterization |
| title_fullStr | An attenuated, adult case of AADC deficiency demonstrated by protein characterization |
| title_full_unstemmed | An attenuated, adult case of AADC deficiency demonstrated by protein characterization |
| title_short | An attenuated, adult case of AADC deficiency demonstrated by protein characterization |
| title_sort | attenuated adult case of aadc deficiency demonstrated by protein characterization |
| topic | Aromatic amino acid decarboxylase AADC deficiency Pyridoxal 5′-phosphate Compound heterozygosis Genotype-phenotype correlation |
| url | http://www.sciencedirect.com/science/article/pii/S2214426924000247 |
| work_keys_str_mv | AT giovannibisello anattenuatedadultcaseofaadcdeficiencydemonstratedbyproteincharacterization AT christiaangjsaris anattenuatedadultcaseofaadcdeficiencydemonstratedbyproteincharacterization AT rossellafranchini anattenuatedadultcaseofaadcdeficiencydemonstratedbyproteincharacterization AT marcelmverbeek anattenuatedadultcaseofaadcdeficiencydemonstratedbyproteincharacterization AT michelaapwillemsen anattenuatedadultcaseofaadcdeficiencydemonstratedbyproteincharacterization AT massimilianoperduca anattenuatedadultcaseofaadcdeficiencydemonstratedbyproteincharacterization AT mariaritabertoldi anattenuatedadultcaseofaadcdeficiencydemonstratedbyproteincharacterization AT giovannibisello attenuatedadultcaseofaadcdeficiencydemonstratedbyproteincharacterization AT christiaangjsaris attenuatedadultcaseofaadcdeficiencydemonstratedbyproteincharacterization AT rossellafranchini attenuatedadultcaseofaadcdeficiencydemonstratedbyproteincharacterization AT marcelmverbeek attenuatedadultcaseofaadcdeficiencydemonstratedbyproteincharacterization AT michelaapwillemsen attenuatedadultcaseofaadcdeficiencydemonstratedbyproteincharacterization AT massimilianoperduca attenuatedadultcaseofaadcdeficiencydemonstratedbyproteincharacterization AT mariaritabertoldi attenuatedadultcaseofaadcdeficiencydemonstratedbyproteincharacterization |