Forskning
Udskriv Udskriv
Switch language
Rigshospitalet - en del af Københavns Universitetshospital
Udgivet

Toward mechanistic models for genotype-phenotype correlations in phenylketonuria using protein stability calculations

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

  1. Myopathy can be a key phenotype of membrin (GOSR2) deficiency

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Expansion of the phenotypic spectrum of de novo missense variants in kinesin family member 1A (KIF1A)

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. A single c.1715G>C calpain 3 gene variant causes dominant calpainopathy with loss of calpain 3 expression and activity

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. From genotype to phenotype: Early prediction of disease severity in argininosuccinic aciduria

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Selection criteria for assembling a pediatric cancer predisposition syndrome gene panel

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Prevalence of Pathogenic Germline DICER1 Variants in Young Individuals Thyroidectomised Due to Goitre - A National Danish Cohort

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Cohort profile and heritability assessment of familial pancreatic cancer: a nation-wide study

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers: an international cohort study

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • Rasmus Scheller
  • Amelie Stein
  • Sofie V Nielsen
  • Frederikke I Marin
  • Anne-Marie Gerdes
  • Miriam Di Marco
  • Elena Papaleo
  • Kresten Lindorff-Larsen
  • Rasmus Hartmann-Petersen
Vis graf over relationer

Phenylketonuria (PKU) is a genetic disorder caused by variants in the gene encoding phenylalanine hydroxylase (PAH), resulting in accumulation of phenylalanine to neurotoxic levels. Here, we analyzed the cellular stability, localization, and interaction with wild-type PAH of 20 selected PKU-linked PAH protein missense variants. Several were present at reduced levels in human cells, and the levels increased in the presence of a proteasome inhibitor, indicating that proteins are proteasome targets. We found that all the tested PAH variants retained their ability to associate with wild-type PAH, and none formed aggregates, suggesting that they are only mildly destabilized in structure. In all cases, PAH variants were stabilized by the cofactor tetrahydrobiopterin (BH4 ), a molecule known to alleviate symptoms in certain PKU patients. Biophysical calculations on all possible single-site missense variants using the full-length structure of PAH revealed a strong correlation between the predicted protein stability and the observed stability in cells. This observation rationalizes previously observed correlations between predicted loss of protein destabilization and disease severity, a correlation that we also observed using new calculations. We thus propose that many disease-linked PAH variants are structurally destabilized, which in turn leads to proteasomal degradation and insufficient amounts of cellular PAH protein.

OriginalsprogEngelsk
TidsskriftHuman Mutation
Vol/bind40
Udgave nummer4
Sider (fra-til)444-457
Antal sider14
ISSN1059-7794
DOI
StatusUdgivet - 1 apr. 2019

Bibliografisk note

© 2019 Wiley Periodicals, Inc.

ID: 58278883