{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T23:22:06Z","timestamp":1790032926630,"version":"4.0.1"},"reference-count":28,"publisher":"BMJ","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"published-print":{"date-parts":[[1998,4]]},"abstract":"<jats:p>In order to elucidate the molecular basis of phenylketonuria (PKU) in Portugal, a detailed study of the Portuguese mutant phenylalanine hydroxylase (PAH) genes was performed. A total of 222 mutant alleles from 111 PKU families were analysed for 26 mutations and restriction fragment length polymorphismlvariable number tandem repeat (RFLP\/VNTR) haplotypes. It was possible to characterise 55% of the mutant alleles, in which 14 different mutations (R261Q, V388M, IVS10nt-11, I65T, P281L, R252W, R158Q, L348V, Y414C, L311P, Y198fsdel22bp, R408W, R270K, and R261X) and three polymorphisms (Q232Q, V245V, and L385L) were identified. A total of 14 different haplotypes were observed, with a high prevalence of haplotype 1 among mutant and normal alleles. The results reported in this study show considerable genetic heterogeneity in the Portuguese PKU population, as has also been described for other southern European populations.<\/jats:p>","DOI":"10.1136\/jmg.35.4.301","type":"journal-article","created":{"date-parts":[[2008,11,10]],"date-time":"2008-11-10T15:37:21Z","timestamp":1226331441000},"page":"301-304","source":"Crossref","is-referenced-by-count":26,"title":["Population genetics of hyperphenylalaninaemia resulting from phenylalanine hydroxylase deficiency in Portugal."],"prefix":"10.1136","volume":"35","author":[{"given":"I","family":"Rivera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Leandro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"U","family":"Lichter-Konecki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I","family":"Tavares de Almeida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M C","family":"Lechner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[1998,4,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/nar\/25.1.139","article-title":"The PAH mutation analysis consortium database: update 1996","volume":"25","author":"Nowacki, P.; Byck, S.; Prevost, L.; Scriver, C.R.","year":"1997","unstructured":"Nowacki P, Byck S, Prevost L, Scriver CR. The PAH mutation analysis consortium database: update 1996. Nucleic Acids Res 1997;25:139-42.","journal-title":"Nucleic Acids Res"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1006\/geno.1993.1295","article-title":"Molecular analysis of phenylketonuria in Denmark: 99% of the mutations detected by denaturing gradient gel electrophoresis","volume":"17","author":"Guldberg, P.; Henriksen, K.F.; Guttler, F.","year":"1993","unstructured":"Guldberg P, Henriksen KF, Guttler F. Molecular analysis of phenylketonuria in Denmark: 99% of the mutations detected by denaturing gradient gel electrophoresis. Genomics 1993;17:141-6.","journal-title":"Genomics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1159\/000472338","article-title":"Origins of hyperphenylalaninemia in Israel","volume":"2","author":"Kleiman, S.; Avigad, S.; Vanagaite, L.","year":"1994","unstructured":"Kleiman S, Avigad S, Vanagaite L, et al. Origins of hyperphenylalaninemia in Israel. EurJ Hum Genet 1994;2: 24-34.","journal-title":"EurJ Hum Genet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1007\/BF00735425","article-title":"Molecular and population genetics of phenylketonuria in Orientals","volume":"17","author":"Okano, Y.; Hase, Y.; Lee, D.H.","year":"1994","unstructured":"Okano Y, Hase Y, Lee DH, et al. Molecular and population genetics of phenylketonuria in Orientals. J Inherit Metab Dis 1994;17:156-9.","journal-title":"J Inherit Metab Dis"},{"key":"ref_5","first-page":"321","article-title":"Mutation profiles of phenylketonuria in Quebec populations: evidence of stratification and novel mutations","volume":"55","author":"Rozen, R.; Mascish, A.; Lambert, M.; Laframboise, R.; Scriver, C.R.","year":"1994","unstructured":"Rozen R, Mascish A, Lambert M, Laframboise R, Scriver CR. Mutation profiles of phenylketonuria in Quebec populations: evidence of stratification and novel mutations. Am3rHum Genet 1994;55:321-6.","journal-title":"Am3rHum Genet"},{"key":"ref_6","first-page":"11","article-title":"Associations between population, phenylketonuria mutations and RFLP haplotypes at the phenylalanine hydroxylase gene: an overview","volume":"6","author":"Scriver, C.R.; John, S.M.W.; Rozen, R.; Eisensmith, R.C.; Woo, S.L.C.","year":"1993","unstructured":"Scriver CR, John SMW, Rozen R, Eisensmith RC, Woo SLC. Associations between population, phenylketonuria mutations and RFLP haplotypes at the phenylalanine hydroxylase gene: an overview. Dev Brain Dysfunct 1993;6: 11-25.","journal-title":"Dev Brain Dysfunct"},{"key":"ref_7","first-page":"627","article-title":"Association between mutations and a VNTR in the human phenylalanine hydroxylase gene","volume":"51","author":"Goltsov, A.A.; Eisensmith, R.C.; Konecki, D.S.; Lichter-Konecki, U.; Woo, S.L.C.","year":"1992","unstructured":"Goltsov AA, Eisensmith RC, Konecki DS, Lichter-Konecki U, Woo SLC. Association between mutations and a VNTR in the human phenylalanine hydroxylase gene. Am Y Hum Genet 1992;51:627-36.","journal-title":"Am Y Hum Genet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1093\/hmg\/2.5.577","article-title":"A single polymorphic STR system in the human phenylalanine hydroxylase gene permits rapid prenatal diagnosis and carrier screening for phenylketonuria","volume":"2","author":"Goltsov, A.A.; Eisensmith, R.C.; Naughten, E.R.","year":"1993","unstructured":"Goltsov AA, Eisensmith RC, Naughten ER, et al. A single polymorphic STR system in the human phenylalanine hydroxylase gene permits rapid prenatal diagnosis and carrier screening for phenylketonuria. Hum Mol Genet 1993;2: 577-81.","journal-title":"Hum Mol Genet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/0888-7543(89)90137-7","article-title":"CpG dinucleotides are mutation hot spots in phenylketonuria","volume":"5","author":"Abadie, V.; Lyonnet, S.; Maurin, N.","year":"1989","unstructured":"Abadie V, Lyonnet S, Maurin N, et al. CpG dinucleotides are mutation hot spots in phenylketonuria. Genomics 1989; 5:936-9.","journal-title":"Genomics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/0888-7543(91)90225-4","article-title":"Phenylketonuria missense mutations in the Mediterranean","volume":"9","author":"Okano, Y.; Wang, T.; Eisensmith, R.C.","year":"1991","unstructured":"Okano Y, Wang T, Eisensmith RC, et al. Phenylketonuria missense mutations in the Mediterranean. Genomics 1991; 9:96-103.","journal-title":"Genomics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/0888-7543(91)90238-A","article-title":"Phenylalanine hydroxylase gene: novel missense mutation in exon 7 causing severe phenylketonuria","volume":"9","author":"Dworniczak, B.; Grudda, K.; Stumper, J.; Bartholome, K.; Aulehla-Scholz, C.; Horst, J.","year":"1991","unstructured":"Dworniczak B, Grudda K, Stumper J, Bartholome K, Aulehla-Scholz C, Horst J. Phenylalanine hydroxylase gene: novel missense mutation in exon 7 causing severe phenylketonuria. Genomics 1991;9: 193-9.","journal-title":"Genomics"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/BF01232824","article-title":"Molecular characterization of PKU allele prevalent in southern Europe and Ireland","volume":"17","author":"Dasovich, M.; Konecki, D.; Lichter-Konecki, U.","year":"1991","unstructured":"Dasovich M, Konecki D, Lichter-Konecki U, et al. Molecular characterization of PKU allele prevalent in southern Europe and Ireland. Somat Cell Mol Genet 1991;17:303-9.","journal-title":"Somat Cell Mol Genet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/0140-6736(91)92584-O","article-title":"Phenylketonuria mutations in southern Europeans","volume":"337","author":"Kalaydjieva, L.; Dworniczak, B.; Aulehla-Scholz, C.","year":"1991","unstructured":"Kalaydjieva L, Dworniczak B, Aulehla-Scholz C, et al. Phenylketonuria mutations in southern Europeans. Lancet 1991;337:865.","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1021\/bi00324a002","article-title":"Nucleotide sequence of a full-length complementary DNA clone and amino acid sequence of human phenylalanine hydroxylase","volume":"24","author":"Kwok, S.C.M.; Ledley, F.D.; DiLella, A.G.","year":"1985","unstructured":"Kwok SCM, Ledley FD, DiLella AG, et al. Nucleotide sequence of a full-length complementary DNA clone and amino acid sequence of human phenylalanine hydroxylase. Biochemistry 1985;24:556-61.","journal-title":"Biochemistry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1073\/pnas.81.7.1991","article-title":"Genomic sequencing","volume":"81","author":"Church, G.M.; Gilbert, W.","year":"1984","unstructured":"Church GM, Gilbert W. Genomic sequencing. Proc Natl Acad Sci USA 1984;81:1991-5.","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref_16","article-title":"PCR detection of the BglII RFLP at the human phenylalanine hydroxylase (PAH) locus","author":"Dworniczak, B.; Wedemeyer, N.; Horst, J.","year":"1991","unstructured":"Dworniczak B, Wedemeyer N, Horst J. PCR detection of the BglII RFLP at the human phenylalanine hydroxylase (PAH) locus. Nucleic Acids Res 1991;19:1958.","journal-title":"Nucleic Acids Res"},{"key":"ref_17","article-title":"PCR detection of the PvuII (Ea) RFLP at the human phenylalanine hydroxylase (PAH) locus","author":"Dworniczak, B.; Wedemeyer, N.; Eigel, A.; Horst, J.","year":"1991","unstructured":"Dworniczak B, Wedemeyer N, Eigel A, Horst J. PCR detection of the PvuII (Ea) RFLP at the human phenylalanine hydroxylase (PAH) locus. Nucleic Acids Res 1991;19: 1958.","journal-title":"Nucleic Acids Res"},{"key":"ref_18","article-title":"PCR detection of the MspI (Aa) RFLP at the human phenylalanine hydroxylase (PAH) locus","author":"Wedemeyer, N.; Dworniczak, B.; Horst, J.","year":"1991","unstructured":"Wedemeyer N, Dworniczak B, Horst J. PCR detection of the MspI (Aa) RFLP at the human phenylalanine hydroxylase (PAH) locus. Nucleic Acids Res 1991;19:1959.","journal-title":"Nucleic Acids Res"},{"key":"ref_19","first-page":"53","article-title":"Restriction enzymebased assays for complete genotyping of phenylketonuria patients","volume":"6","author":"Eiken, H.G.; Knappskog, P.M.; Apold, J.","year":"1993","unstructured":"Eiken HG, Knappskog PM, Apold J. Restriction enzymebased assays for complete genotyping of phenylketonuria patients. Dev Brain Dysfunct 1993;6:53-9.","journal-title":"Dev Brain Dysfunct"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5463","DOI":"10.1073\/pnas.74.12.5463","article-title":"DNA sequencing with chain-terminating inhibitors","volume":"75","author":"Sanger, F.; Nicklen, S.; Caulson, A.R.","year":"1977","unstructured":"Sanger F, Nicklen S, Caulson AR. DNA sequencing with chain-terminating inhibitors. Proc Nad Acad Sci USA 1977;75:5463-7.","journal-title":"Proc Nad Acad Sci USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1093\/hmg\/2.10.1703","article-title":"Mutational spectrum of phenylalanine hydroxylase deficiency in Sicily: implications for diagnosis of hyperphenylalaninemia in Southern Europe","volume":"2","author":"Guldberg, P.; Romano, V.; Ceratto, N.","year":"1993","unstructured":"Guldberg P, Romano V, Ceratto N, et al. Mutational spectrum of phenylalanine hydroxylase deficiency in Sicily: implications for diagnosis of hyperphenylalaninemia in Southern Europe. Hum Mol Genet 1993;2:1703-7.","journal-title":"Hum Mol Genet"},{"key":"ref_22","first-page":"34","article-title":"Spectrum and origin of phenylketonuria mutations in Spain","volume":"407","author":"Perez, B.; Desviat, L.R.; De Lucca, M.; Ugarte, M.","year":"1994","unstructured":"Perez B, Desviat LR, De Lucca M, Ugarte M. Spectrum and origin of phenylketonuria mutations in Spain. Acta Paediatr Scand Suppl 1994;407:34-6.","journal-title":"Acta Paediatr Scand Suppl"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/BF00207045","article-title":"Linkage disequilibrium between phenylketonuria and RFLP haplotype 1 at the phenylalanine hydroxylase locus in Portugal","volume":"89","author":"Caillaud, C.; Vilarinho, L.; Vilarinho, A.","year":"1992","unstructured":"Caillaud C, Vilarinho L, Vilarinho A, et al. Linkage disequilibrium between phenylketonuria and RFLP haplotype 1 at the phenylalanine hydroxylase locus in Portugal. Hum Genet 1992;89:69-72.","journal-title":"Hum Genet"},{"key":"ref_24","first-page":"573","article-title":"Preliminary mutation analysis in the phenylalanine hydroxylase gene in Greek PKU and HPA patients","volume":"94","author":"Traeger-Synodinos, J.; Kanavakis, E.; Kalogerakou, M.; Soulpi, K.; Missiou-Tsangaraki, S.; Kattamis, C.","year":"1994","unstructured":"Traeger-Synodinos J, Kanavakis E, Kalogerakou M, Soulpi K, Missiou-Tsangaraki S, Kattamis C. Preliminary mutation analysis in the phenylalanine hydroxylase gene in Greek PKU and HPA patients. Hum Genet 1994;94:573-5.","journal-title":"Hum Genet"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s004390050150","article-title":"Preliminary studies on the molecular basis of hyperphenylalaninemia in Egypt","volume":"98","author":"Hashem, N.; Bosco, P.; Chiavetta, V.; Cali, F.; Ceratto, N.; Romano, V.","year":"1996","unstructured":"Hashem N, Bosco P, Chiavetta V, Cali F, Ceratto N, Romano V. Preliminary studies on the molecular basis of hyperphenylalaninemia in Egypt. Hum Genet 1996;98:3-6.","journal-title":"Hum Genet"},{"key":"ref_26","first-page":"337","article-title":"Evidence in Latin Atimoenriwictahofhirgehcuirnrevnictreo orfeVs3id8u8alM, actaipvihteyn. yAlkmetJofnHuruima muta- Genet","volume":"57","author":"Desviat, L.R.; Perez, B.; De Lucca, M.","year":"1995","unstructured":"Desviat LR, Perez B, De Lucca M, et al. Evidence in Latin Atimoenriwictahofhirgehcuirnrevnictreo orfeVs3id8u8alM,actaipvihteyn. yAlkmetJofnHuruima muta- Genet 1995;57:337-42."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1002\/(SICI)1098-1004(1996)8:3<262::AID-HUMU10>3.0.CO;2-0","article-title":"Mutation analysis of phenylketonuria in south Brazil","volume":"8","author":"Perez, B.; Desviat, L.R.; De Lucca, M.","year":"1996","unstructured":"Perez B, Desviat LR, De Lucca M, et al. Mutation analysis of phenylketonuria in south Brazil. Hum Mutat 1996;8: 262-4.","journal-title":"Hum Mutat"},{"key":"ref_28","first-page":"227","article-title":"Molecular basis of non-PKU A403V, a hmyupteartpihoennywliatlhanhiingahemrieasiidnuaSlpaaicnt:iviptrye.vaJleInncheeroitf Metab Dis","volume":"19","author":"Desviat, L.R.; Perez, B.; Ugarte, M.","year":"1996","unstructured":"Desviat LR, Perez B, Ugarte M. Molecular basis of non-PKU A403V, a hmyupteartpihoennywliatlhanhiingahemrieasiidnuaSlpaaicnt:iviptrye.vaJleInncheeroitf Metab Dis 1996;19:227-30."}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg.35.4.301","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T06:19:35Z","timestamp":1760768375000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg.35.4.301"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1998,4]]},"references-count":28,"journal-issue":{"issue":"4","published-online":{"date-parts":[[1998,4,1]]},"published-print":{"date-parts":[[1998,4]]}},"alternative-id":["10.1136\/jmg.35.4.301"],"URL":"https:\/\/doi.org\/10.1136\/jmg.35.4.301","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[1998,4]]}}}