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Titolo:
Homomeric and heteromeric interactions between wild-type and mutant phenylalanine hydroxylase subunits: Evaluation of two-hybrid approaches for functional analysis of mutations causing hyperphenylalaninemia
Autore:
Waters, PJ; Scriver, CR; Parniak, MA;
Indirizzi:
McGill Univ, Montreal Childrens Hosp, Inst Res, DeBelle Lab Biochem Genet,Westmount, PQ H3Z 2Z3, Canada McGill Univ Westmount PQ Canada H3Z 2Z3 net,Westmount, PQ H3Z 2Z3, Canada McGill Univ, Dept Human Genet, Montreal, PQ, Canada McGill Univ Montreal PQ Canada v, Dept Human Genet, Montreal, PQ, Canada McGill Univ, Dept Pediat, Montreal, PQ H3A 2T5, Canada McGill Univ Montreal PQ Canada H3A 2T5 diat, Montreal, PQ H3A 2T5, Canada McGill Univ, Dept Biol, Montreal, PQ H3A 1B1, Canada McGill Univ MontrealPQ Canada H3A 1B1 Biol, Montreal, PQ H3A 1B1, Canada McGill Univ, Dept Med, Montreal, PQ H3A 1B1, Canada McGill Univ Montreal PQ Canada H3A 1B1 Med, Montreal, PQ H3A 1B1, Canada Lady Davis Inst Med Res, Montreal, PQ, Canada Lady Davis Inst Med Res Montreal PQ Canada Med Res, Montreal, PQ, Canada
Titolo Testata:
MOLECULAR GENETICS AND METABOLISM
fascicolo: 3, volume: 73, anno: 2001,
pagine: 230 - 238
SICI:
1096-7192(200107)73:3<230:HAHIBW>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
EXPRESSION ANALYSIS; MISSENSE MUTATIONS; GENE PAH; PHENYLKETONURIA; DEGRADATION; PHENOTYPE; MECHANISM; PROTEIN; AGGREGATION; DEHYDRATASE;
Keywords:
phenylalanine hydroxylase; phenylketonuria; hyperphenylalaninemia; missense mutations; in vitro expression; protein-protein interactions; yeast two-hybrid; dihydropteridine reductase; pterin-4 alpha-carbinolamine dehydratase; dimerization cofactor for HNF-1 alpha (DCoH);
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
26
Recensione:
Indirizzi per estratti:
Indirizzo: Waters, PJ McGill Univ, Montreal Childrens Hosp, Inst Res, DeBelle Lab Biochem Genet,PT-413,4060 St Catherine St West, Westmount, PQ H3Z 2Z3, Canada McGill Univ PT-413,4060 St Catherine St West Westmount PQ Canada H3Z 2Z3
Citazione:
P.J. Waters et al., "Homomeric and heteromeric interactions between wild-type and mutant phenylalanine hydroxylase subunits: Evaluation of two-hybrid approaches for functional analysis of mutations causing hyperphenylalaninemia", MOL GEN MET, 73(3), 2001, pp. 230-238

Abstract

Phenylketonuria (PKU) is caused by mutations in the phenylalanine hydroxylase gene (PAH), while mutations in genes encoding the two enzymes (dihydropteridine reductase, DHPR, and pterin-4-alpha -carbinolamine dehydratase, PCD) required for recycling of its cofactor, tetrahydrobiopterin (BH4), causeother rarer disease forms of hyperphenylalaninemia. We have applied a yeast two-hybrid method, in which protein-protein interactions are measured by four reporter gene constructs, to the analysis of six PKU-associated PAH missense mutations (F39L, K42I, L48S, I65T, A104D, and R157N). By studying homomeric interactions between mutant PAH subunits, we show that this system is capable of detecting quite subtle aberrations in PAH oligomerization caused by missense mutations and that the observed results generally correlatewith the severity of the mutation as determined by other expression systems. The mutant PAH subunits are also shown in this system to be able to interact with wild-type PAH subunits, pointing to an explanation for apparent dominant negative effects previously observed in obligate heterozygotes for PKU mutations. Based on our findings, the applications and limitations of two-hybrid approaches in understanding mechanisms by which PAH missense mutations exert their pathogenic effects are discussed. We have also used this technique to demonstrate homomeric interactions between wild-type DHPR subunits and between wild-type PCD subunits. These data provide a basis for functional studies on HPA-associated mutations affecting these enzymes. (C) 2001 Academic Press.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 15/07/20 alle ore 08:19:19