Phenylalanine hydroxylase gene mutations in the United States

Report from the Maternal PKU Collaborative Study

P. Guldberg, H. L. Levy, W. B. Hanley, R. Koch, Reuben Matalon, B. M. Rouse, F. Trefz, F. De la Cruz, K. F. Henriksen, F. Guttler

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

The major cause of hyperphenylalaninemia is mutations in the gene encoding phenylalanine hydroxylase (PAH). The known mutations have been identified primarily in European patients. The purpose of this study was to determine the spectrum of mutations responsible for PAH deficiency in the United States. One hundred forty-nine patients enrolled in the Maternal PKU Collaborative Study were subjects for clinical and molecular investigations. PAH gene mutations associated with phenylketonuria (PKU) or mild hyperphenylalaninemia (MHP) were identified on 279 of 294 independent mutant chromosomes, a diagnostic efficiency of 95%. The spectrum is composed of 71 different mutations, including 47 missense mutations, 11 splice mutations, 5 nonsense mutations, and 8 microdeletions. Sixteen previously unreported mutations were identified. Among the novel mutations, five were found in patients with MHP, and the remainder were found in patients with PKU. The most common mutations were R408W, IVS12nt1g→a, and Y414C, accounting for 18.7%, 7.8%, and 5.4% of the mutant chromosomes, respectively. Thirteen mutations had relative frequencies of 1%-5%, and 55 mutations each had frequencies ≤1%. The mutational spectrum corresponded to that observed for the European ancestry of the U.S. population. To evaluate the extent of allelic variation at the PAH locus within the United States in comparison with other populations, we used allele frequencies to calculate the homozygosity for 11 populations where >90% ascertainment of mutations has been obtained. The United States was shown to contain one of the most heterogeneous populations, with homozygosity values similar to Sicily and ethnically mixed sample populations in Europe. The extent of allelic heterogeneity must be a major determining factor in the choice of mutation- detection methodology for molecular diagnosis in PAH deficiency.

Original languageEnglish (US)
Pages (from-to)84-94
Number of pages11
JournalAmerican Journal of Human Genetics
Volume59
Issue number1
StatePublished - 1996
Externally publishedYes

Fingerprint

Maternal Phenylketonuria
Phenylalanine Hydroxylase
Phenylketonurias
Mutation
Genes
Population
Chromosomes
Sicily
Nonsense Codon
Missense Mutation

ASJC Scopus subject areas

  • Genetics

Cite this

Guldberg, P., Levy, H. L., Hanley, W. B., Koch, R., Matalon, R., Rouse, B. M., ... Guttler, F. (1996). Phenylalanine hydroxylase gene mutations in the United States: Report from the Maternal PKU Collaborative Study. American Journal of Human Genetics, 59(1), 84-94.

Phenylalanine hydroxylase gene mutations in the United States : Report from the Maternal PKU Collaborative Study. / Guldberg, P.; Levy, H. L.; Hanley, W. B.; Koch, R.; Matalon, Reuben; Rouse, B. M.; Trefz, F.; De la Cruz, F.; Henriksen, K. F.; Guttler, F.

In: American Journal of Human Genetics, Vol. 59, No. 1, 1996, p. 84-94.

Research output: Contribution to journalArticle

Guldberg, P, Levy, HL, Hanley, WB, Koch, R, Matalon, R, Rouse, BM, Trefz, F, De la Cruz, F, Henriksen, KF & Guttler, F 1996, 'Phenylalanine hydroxylase gene mutations in the United States: Report from the Maternal PKU Collaborative Study', American Journal of Human Genetics, vol. 59, no. 1, pp. 84-94.
Guldberg, P. ; Levy, H. L. ; Hanley, W. B. ; Koch, R. ; Matalon, Reuben ; Rouse, B. M. ; Trefz, F. ; De la Cruz, F. ; Henriksen, K. F. ; Guttler, F. / Phenylalanine hydroxylase gene mutations in the United States : Report from the Maternal PKU Collaborative Study. In: American Journal of Human Genetics. 1996 ; Vol. 59, No. 1. pp. 84-94.
@article{6da1d111c0bf40a7b33c903594a6f9ef,
title = "Phenylalanine hydroxylase gene mutations in the United States: Report from the Maternal PKU Collaborative Study",
abstract = "The major cause of hyperphenylalaninemia is mutations in the gene encoding phenylalanine hydroxylase (PAH). The known mutations have been identified primarily in European patients. The purpose of this study was to determine the spectrum of mutations responsible for PAH deficiency in the United States. One hundred forty-nine patients enrolled in the Maternal PKU Collaborative Study were subjects for clinical and molecular investigations. PAH gene mutations associated with phenylketonuria (PKU) or mild hyperphenylalaninemia (MHP) were identified on 279 of 294 independent mutant chromosomes, a diagnostic efficiency of 95{\%}. The spectrum is composed of 71 different mutations, including 47 missense mutations, 11 splice mutations, 5 nonsense mutations, and 8 microdeletions. Sixteen previously unreported mutations were identified. Among the novel mutations, five were found in patients with MHP, and the remainder were found in patients with PKU. The most common mutations were R408W, IVS12nt1g→a, and Y414C, accounting for 18.7{\%}, 7.8{\%}, and 5.4{\%} of the mutant chromosomes, respectively. Thirteen mutations had relative frequencies of 1{\%}-5{\%}, and 55 mutations each had frequencies ≤1{\%}. The mutational spectrum corresponded to that observed for the European ancestry of the U.S. population. To evaluate the extent of allelic variation at the PAH locus within the United States in comparison with other populations, we used allele frequencies to calculate the homozygosity for 11 populations where >90{\%} ascertainment of mutations has been obtained. The United States was shown to contain one of the most heterogeneous populations, with homozygosity values similar to Sicily and ethnically mixed sample populations in Europe. The extent of allelic heterogeneity must be a major determining factor in the choice of mutation- detection methodology for molecular diagnosis in PAH deficiency.",
author = "P. Guldberg and Levy, {H. L.} and Hanley, {W. B.} and R. Koch and Reuben Matalon and Rouse, {B. M.} and F. Trefz and {De la Cruz}, F. and Henriksen, {K. F.} and F. Guttler",
year = "1996",
language = "English (US)",
volume = "59",
pages = "84--94",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "1",

}

TY - JOUR

T1 - Phenylalanine hydroxylase gene mutations in the United States

T2 - Report from the Maternal PKU Collaborative Study

AU - Guldberg, P.

AU - Levy, H. L.

AU - Hanley, W. B.

AU - Koch, R.

AU - Matalon, Reuben

AU - Rouse, B. M.

AU - Trefz, F.

AU - De la Cruz, F.

AU - Henriksen, K. F.

AU - Guttler, F.

PY - 1996

Y1 - 1996

N2 - The major cause of hyperphenylalaninemia is mutations in the gene encoding phenylalanine hydroxylase (PAH). The known mutations have been identified primarily in European patients. The purpose of this study was to determine the spectrum of mutations responsible for PAH deficiency in the United States. One hundred forty-nine patients enrolled in the Maternal PKU Collaborative Study were subjects for clinical and molecular investigations. PAH gene mutations associated with phenylketonuria (PKU) or mild hyperphenylalaninemia (MHP) were identified on 279 of 294 independent mutant chromosomes, a diagnostic efficiency of 95%. The spectrum is composed of 71 different mutations, including 47 missense mutations, 11 splice mutations, 5 nonsense mutations, and 8 microdeletions. Sixteen previously unreported mutations were identified. Among the novel mutations, five were found in patients with MHP, and the remainder were found in patients with PKU. The most common mutations were R408W, IVS12nt1g→a, and Y414C, accounting for 18.7%, 7.8%, and 5.4% of the mutant chromosomes, respectively. Thirteen mutations had relative frequencies of 1%-5%, and 55 mutations each had frequencies ≤1%. The mutational spectrum corresponded to that observed for the European ancestry of the U.S. population. To evaluate the extent of allelic variation at the PAH locus within the United States in comparison with other populations, we used allele frequencies to calculate the homozygosity for 11 populations where >90% ascertainment of mutations has been obtained. The United States was shown to contain one of the most heterogeneous populations, with homozygosity values similar to Sicily and ethnically mixed sample populations in Europe. The extent of allelic heterogeneity must be a major determining factor in the choice of mutation- detection methodology for molecular diagnosis in PAH deficiency.

AB - The major cause of hyperphenylalaninemia is mutations in the gene encoding phenylalanine hydroxylase (PAH). The known mutations have been identified primarily in European patients. The purpose of this study was to determine the spectrum of mutations responsible for PAH deficiency in the United States. One hundred forty-nine patients enrolled in the Maternal PKU Collaborative Study were subjects for clinical and molecular investigations. PAH gene mutations associated with phenylketonuria (PKU) or mild hyperphenylalaninemia (MHP) were identified on 279 of 294 independent mutant chromosomes, a diagnostic efficiency of 95%. The spectrum is composed of 71 different mutations, including 47 missense mutations, 11 splice mutations, 5 nonsense mutations, and 8 microdeletions. Sixteen previously unreported mutations were identified. Among the novel mutations, five were found in patients with MHP, and the remainder were found in patients with PKU. The most common mutations were R408W, IVS12nt1g→a, and Y414C, accounting for 18.7%, 7.8%, and 5.4% of the mutant chromosomes, respectively. Thirteen mutations had relative frequencies of 1%-5%, and 55 mutations each had frequencies ≤1%. The mutational spectrum corresponded to that observed for the European ancestry of the U.S. population. To evaluate the extent of allelic variation at the PAH locus within the United States in comparison with other populations, we used allele frequencies to calculate the homozygosity for 11 populations where >90% ascertainment of mutations has been obtained. The United States was shown to contain one of the most heterogeneous populations, with homozygosity values similar to Sicily and ethnically mixed sample populations in Europe. The extent of allelic heterogeneity must be a major determining factor in the choice of mutation- detection methodology for molecular diagnosis in PAH deficiency.

UR - http://www.scopus.com/inward/record.url?scp=0029895020&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029895020&partnerID=8YFLogxK

M3 - Article

VL - 59

SP - 84

EP - 94

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 1

ER -