Functional and structural characterization of novel mutations and genotype-phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy
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Functional and structural characterization of novel mutations and genotype-phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy (1923 views)

Daniele A, Scala I, Cardillo G, Pennino C, Ungaro C, Sibilio M, Parenti G, Esposito L, Zagari A, Andria G, Salvatore F

Febs Journal (ISSN: 1742-464x), 2009 Apr; 276(7): 2048-2059.

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Paper type: Journal Article,

Impact factor: 3.042, 5-year impact factor: 3.276

Url: http://www.scopus.com/inward/record.url?eid=2-s2.0-62149087350&partnerID=40&md5=7130d08828fde13c4335db8d52b99d56

Keywords: Bh4-Responsiveness, Hyperphenylalaninemia, Molecular Epidemiology, Pah Mutation Functional Analysis, Pah Structural Alterations, Phenylketonuria, Phenylalanine 4 Monooxygenase, Adolescent, Adult, Article, Child, Controlled Study, Enzyme Active Site, Enzyme Activity, Exon, Female, Gene Mutation, Genotype Phenotype Correlation, Human, In Vivo Study, Italy, Major Clinical Study, Preschool Child, Priority Journal, Protein Stability, Amino Acid Sequence, Dihydropteridine Reductase, Models, Molecular Sequence Data, Phenylalanine Hydroxylase, Protein Conformation,

Affiliations:
*** IBB - CNR ***

CEINGE-Biotecnologie Avanzate Scarl, Naples, Italy
IRCCS - Fondazione SDN, Naples, Italy
Dipartimento di Scienze per la Salute, Università Del Molise, Campobasso, Italy
Dipartimento di Pediatria, Università di Napoli 'Federico II', Naples, Italy
Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli 'Federico II', Naples, Italy
CNR - Istituto di Biostrutture e Bioimmagini, Naples, Italy
CEINGE Biotecnologie, Avanzate S.C.a R.l., via Comunale Margherita 482, I-80145 Napoli, Italy


References:
Not available.
Functional and structural characterization of novel mutations and genotype-phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy

Hyperphenylalaninemia (Online Mendelian Inheritance in Man (R) database: 261600) is an autosomal recessive disorder mainly due to mutations in the gene for phenylalanine hydroxylase; the most severe form of hyperphenylalaninemia is classic phenylketonuria. We sequenced the entire gene for phenylalanine hydroxylase in 51 unrelated hyperphenylalaninemia patients from Southern Italy. The entire locus was genotyped in 46 out of 51 hyperphenylalaninemia patients, and 32 different disease-causing mutations were identified. The pathologic nature of two novel gene variants, namely, c.707-2delA and p.Q301P, was demonstrated by in vitro studies. c.707-2delA is a splicing mutation that involves the accepting site of exon 7; it causes the complete skipping of exon 7 and results in the truncated p.T236MfsX60 protein. The second gene variant, p.Q301P, has very low residual enzymatic activity (similar to 4.4%), which may be ascribed, in part, to a low expression level (8-10%). Both the decreased enzyme activity and the low expression level are supported by analysis of the 3D structure of the molecule. The putative structural alterations induced by p.Q301P are compatible with protein instability and perturbance of monomer interactions within dimers and tetramers, although they do not affect the catalytic site. In vivo studies showed tetrahydrobiopterin responsiveness in the p.Q301P carrier but not in the c.707-2delA carrier. We next investigated genotype-phenotype correlations and found that genotype was a good predictor of phenotype in 76% of patients. However, genotype-phenotype discordance occurred in approximately 25% of our patients, mainly those bearing mutations p.L48S, p.R158Q, p.R261Q and p.P281L.
Functional and structural characterization of novel mutations and genotype-phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy

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Functional and structural characterization of novel mutations and genotype-phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy

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Esposito G, Imperato MR, Ieno L, Sorvillo R, Benigno V, Parenti G, Parini R, Vitagliano L, Zagari A, Salvatore F
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Impact Factor: 5.956
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Daniele A, Cardillo G, Pennino C, Carbone MT, Scognamiglio D, Esposito L, Correra A, Castaldo G, Zagari A, Salvatore F
* Five human phenylalanine hydroxylase proteins identified in mild hyperphenylalaninemia patients are disease-causing variants (1685 views)
Bba-Gen Subjects (ISSN: 0925-4439, 0006-3002, 1570-9639), 2008 Jun; 1782(6): 378-384.
Impact Factor: 2.233
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2 Records (2 excluding Abstracts).
Total impact factor: 8.189 (8.189 excluding Abstracts).
Total 5 year impact factor: 9.028 (9.028 excluding Abstracts).

Last modified by Marco Comerci on Sunday 12 July 2020, 13:15:02
1923 views. Last view on Saturday 19 July 2025, 7:07:07