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ABSTRACT Phenylalanine hydroxylase (PAH) is the enzyme that converts phenylalanine to tyrosine as a rate-limiting step in phenylalanine catabolism and protein and neurotransmitter
biosynthesis. Over 300 mutations have been identified in the gene encoding PAH that result in a deficient enzyme activity and lead to the disorders hyperphenylalaninaemia and
phenylketonuria. The determination of the crystal structure of PAH now allows the determination of the structural basis of mutations resulting in PAH deficiency. We present an analysis of
the structural basis of 120 mutations with a ‘classified’ biochemical phenotype and/or available _IN VITRO_ expression data. We find that the mutations can be grouped into five structural
categories, based on the distinct expected structural and functional effects of the mutations in each category. Missense mutations and small amino acid deletions are found in three
categories: ‘active site mutations’, ‘dimer interface mutations’, and ‘domain structure mutations’. Nonsense mutations and splicing mutations form the category of ‘proteins with truncations
and large deletions’. The final category, ‘fusion proteins’, is caused by frameshift mutations. We show that the structural information helps formulate some rules that will help predict the
likely effects of unclassified and newly discovered mutations: proteins with truncations and large deletions, fusion proteins and active site mutations generally cause severe phenotypes;
domain structure mutations and dimer interface mutations spread over a range of phenotypes, but domain structure mutations in the catalytic domain are more likely to be severe than domain
structure mutations in the regulatory domain or dimer interface mutations. SIMILAR CONTENT BEING VIEWED BY OTHERS LOSS-OF-FUNCTION, GAIN-OF-FUNCTION AND DOMINANT-NEGATIVE MUTATIONS HAVE
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MOLECULAR AND PHENOTYPIC IMPACT OF AMINO ACID VARIANTS WITH MUTPRED2 Article Open access 20 November 2020 ARTICLE PDF AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Structural Biology
Laboratory, St Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia Ian G Jennings & Bostjan Kobe * Mutation Research Centre, Fitzroy, Victoria, Australia Richard
GH Cotton Authors * Ian G Jennings View author publications You can also search for this author inPubMed Google Scholar * Richard GH Cotton View author publications You can also search for
this author inPubMed Google Scholar * Bostjan Kobe View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Bostjan Kobe.
RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Jennings, I., Cotton, R. & Kobe, B. Structural interpretation of mutations in phenylalanine
hydroxylase protein aids in identifying genotype–phenotype correlations in phenylketonuria. _Eur J Hum Genet_ 8, 683–696 (2000). https://doi.org/10.1038/sj.ejhg.5200518 Download citation *
Received: 18 February 2000 * Revised: 18 April 2000 * Accepted: 27 April 2000 * Published: 31 August 2000 * Issue Date: 01 September 2000 * DOI: https://doi.org/10.1038/sj.ejhg.5200518 SHARE
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clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * genotype–phenotype correlations * hyperphenylalaninaemia * phenylalanine * hydroxylase *
phenylketonuria * X-ray crystal structure