Therapeutic Development Research for Phenylketonuria (PKU)

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Testing for PAH Mutations

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Mild PKU

PKU patients with BH4 responsive mutations studied, their location/effect on the PAH structure
PAH cDNA nucleotide change PAH mutation Structural contacts/ comments Metabolic phenotype (homozygotes and functional hemizygotes) % decrease in L-Phe levels after 24h in patients with BH4-responsive genotypes
c.117C>G F39L In hydrophobic core of RD formed by Leu37, Leu41, Val51, Ile65, Phe79, Leu98, Ile102, Ala104 and Leu106. Substitution to a smaller Leu may change the core structure and destabilize RD. Mild to classical PKU F39L/R408W F39L/F55fsdelT F39L/F55fsdelT 44.3
c.194T>C I65T In hydrophobic core of RD. Substitution to a more polar Thr may distort the hydrophobic packing in the RD core. Non-PKU HPA to classical PKU I65T/R68S I65T/R408W I65T/R408W 23.2
c.204A>T R68S H-bonds to Ser67, and stabilizes secondary structure of Rb2. In tetramer model Arg68 is close to Tyr216 from molecule C. Substitution to Ser may disrupt H-bond and dimer/tetramer interactions. Mild PKU R68S/R408W R68S/I65T 40.7
c.311C>A H170D On surface of CD, close to TD and RD. Substitution into an Asp may disrupt a H-bond to Arg241 at the start of Cb1. Non-PKU HPA H170D/IVS1nt 5g>a 68.2
C.533A>G E178G On surface of CD. Substitution to a small and flexible hydrophobic residue may be very unfavorable, as it can change fold of CD core, which is important for maintaining proper catalytic function. Non-PKU HPA E178G/IVS10nt-11g>a 45.8
c.569T>C V190A Close to L-Phe substrate binding site (7.1). Important for proper substrate orientation for catalysis. - - -
c.782G>A R261Q In loop between Ca6 and Cb2. Interacts with Gln304 and Thr238 by H-bonds. Close to Tyr417 in tetrameric model. A substitution would disrupt H-bonds to Gln304 and Thr238 which stabilizes the secondary structure in the active site, and potentially interfere with proper dimer/tetramer formation. Variant PKU to classical PKU R261Q/R408W R261Q/L308F 17.3
c.898C>T A300S Close to Thr 238. Not enough room for larger sidechain of Ser. May change polarity in CD core. Non-PKU HPA A300S/R408W 58.7
c.922C>T L308F Close to TD Val412 and Tyr414, and CD Ala259 and Glu305. No room for Phe sidechain. Substitution would push TD away. Mutation may interfere with proper dimer/tetramer formation. - L308F/R261Q 71.9
c.937G>A A313T Close to TD Ile406 and Pro407. Mutation may interfere with proper dimer/tetramer formation. Mild PKU - -
c.1117G>A A373T Close to Phe402 and Lys320. Mutation may interfere with proper dimer/tetramer formation. Non-PKU HPA - -
c.1162G>A V388M Val388 is located to surface of monomer, close to other monomer of dimmer. Mutation to Met may cause disturbances in dimerization. Mild to moderate PKU - -
c.1169A>G E390G No contacts. On surface, pointing towards molecule B. Substitution to Gly induce local distortions in CD. Non-PKU HPA E390G/IVS12nt1g>a 70.2
c.1219C>T P407S Pro may be important for positioning TD helix. Mutation may interfere with proper dimer/tetramer formation. Non-PKU HPA P407S/R408W 45.2
c.1241A>G Y414C Stacks between Pro416 (TD) and Phe260 (CD). Important for keeping TD close to CD. Mutation may interfere with proper dimer/tetramer formation. Non-PKU HPA to variant PKU Y414C/R408W Y414C/R408W Y414C/IVS7nt5g>a 20.5

Classical PKU and Enzyme Replacement Therapy