Publication
Article Metrics
Citations
Online attention
Role of protein structure in variant annotation: structural insight of mutations causing 6-pyruvoyl-tetrahydropterin synthase deficiency
DOI:
10.1016/j.pathol.2018.11.011
Authors:
Joao R. C.
Muniz
(Structural Genomics Consortium, University of Oxford; University of Sao Paulo)
,
Natalie Wing-Sum
Szeto
(The Chinese University of Hong Kong)
,
Rebecca
Frise
(Structural Genomics Consortium, University of Oxford)
,
Wen Hwa
Lee
(Structural Genomics Consortium, University of Oxford)
,
Xian-Song
Wang
(The Chinese University of Hong Kong)
,
Beat
Thöny
(University Children's Hospital, Zurich)
,
Nastassja
Himmelreich
(University Children's Hospital, Heidelberg)
,
Nenad
Blau
(University Children's Hospital, Heidelberg)
,
Kwang-Jen
Hsiao
(Taipei Veterans General Hospital; Preventive Medicine Foundation, Taipei; Taipei City Hospital)
,
Tze-Tze
Liu
(Taipei City Hospital; National Yang-Ming University)
,
Opher
Gileadi
(Structural Genomics Consortium, University of Oxford)
,
Udo
Oppermann
(Structural Genomics Consortium, University of Oxford; Oxford Biomedical Research Unit)
,
Frank
Von Delft
(Structural Genomics Consortium, University of Oxford; Diamond Light Source; University of Johannesburg)
,
Wyatt
Yue
(Structural Genomics Consortium, University of Oxford)
,
Nelson Leung-Sang
Tang
(The Chinese University of Hong Kong)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Pathology
State:
Published (Approved)
Published:
March 2019
Abstract: Genetic defects on 6-pyruvoyl-tetrahydropterin synthase (PTPS) are the most prevalent cause of hyperphenylalaninaemia not due to phenylalanine hydrolyase deficiency (phenylketonuria). PTPS catalyses the second step of tetrahydrobiopterin (BH4) cofactor biosynthesis, and its deficiency represents the most common form of BH4 deficiency. Untreated PTPS deficiency results in depletion of the neurotransmitters dopamine, catecholamine and serotonin causing neurological symptoms. We archived reported missense variants of the PTS gene. Common in silico algorithms were used to predict the effects of such variants, and substantial proportions (up to 19%) of the variants were falsely classified as benign or uncertain. We have determined the crystal structure of the human PTPS hexamer, allowing another level of interpretation to understand the potential deleterious consequences of the variants from a structural perspective. The in silico and structure approaches appear to be complimentary and may provide new insights that are not available from each alone. Information from the protein structure suggested that the variants affecting amino acid residues required for interaction between monomeric subunits of the PTPS hexamer were those misclassified as benign by in silico algorithms. Our findings illustrate the important utility of 3D protein structure in interpretation of variants and also current limitations of in silico prediction algorithms. However, software to analyse mutation in the perspective of 3D protein structure is far less readily available than other in silico prediction tools.
Journal Keywords: 3D protein structure; mutation analysis; in silico prediction
Diamond Keywords: Enzymes
Subject Areas:
Biology and Bio-materials
Facility: Swiss Light Source
Added On:
13/03/2019 08:33
Discipline Tags:
Non-Communicable Diseases
Health & Wellbeing
Structural biology
Life Sciences & Biotech
Technical Tags: