Tight linkage between a splicing mutation and a specific DNA haplotype in phenylketonuria

DiLella, Anthony G.; Marvit, J.; Lidsky, Alan S.; Güttler, Flemming; Woo, Savio L. C.

doi:10.1038/322799a0

Cited by 217 publications

(93 citation statements)

References 14 publications

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“…These are absolutely conserved and required for accurate splicing of nuclear pre-mRNA (25,26). Mutations at the GT dinucleotide ofthe 5' splice site have been reported to cause skipping ofthe preceding exon (27)(28)(29)(30)(31). We concluded that the substitution of GT dinucleotide for TT in the 5' splice site of intron 8 caused the skipping of exon 8.…”

Section: Discussionmentioning

confidence: 86%

Identification of three mutant alleles of the gene for mitochondrial acetoacetyl-coenzyme A thiolase. A complete analysis of two generations of a family with 3-ketothiolase deficiency.

Fukao

Yamaguchi²,

Orii³

et al. 1992

J. Clin. Invest.

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3-Ketothiolase deficiency (3KTD) stems from a deficiency of mitochondrial acetoacetyl-coenzyme A thiolase (T2). We analyzed the molecular basis of 3KTD in two generations of a family. A boy (patient 2, GK04), his father (patient 1, GK05), his mother, and his brother were studied; three mutant alleles of T2 gene were identified. Patient 1 is a compound heterozygote: one allele has a point mutation of G to A at position 547 on his T2 cDNA, causing Gly1" to Arg substitution of the mature T2 subunit, and the other allele has GT to TI transition at the 5' splice site of intron 8, causing exon 8's skipping of the T2 cDNA. Patient 2 is also a compound heterozygote: one allele inherited from his mother has AG to CG transition at the 3' splice site of intron 10, causing exon 1l's skipping of the T2 cDNA, and the other allele derived from patient 1 has the G to A mutation (Gly to Arg). The brother of patient 2 is an obligatory carrier with the mutant allele causing the exon 8 skipping. This report seems to be the first complete molecular definition of 3KTD at the gene level. (J. Clin. Invest. 1992.89:474-479.)

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Section: Discussionmentioning

confidence: 86%

Identification of three mutant alleles of the gene for mitochondrial acetoacetyl-coenzyme A thiolase. A complete analysis of two generations of a family with 3-ketothiolase deficiency.

Fukao

Yamaguchi²,

Orii³

et al. 1992

J. Clin. Invest.

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“…We demonstrated a point mutation in the canonical 5' splice donor site of the first intron of the PBGD gene (Go-A). Similar mutations have been shown (19,20) to completely abolish normal splicing. Since the first intron interrupts the sequence coding for the nonerythroid isoform of PBGD (7), it is to be expected that an abnormal splicing leads to detrimental effects on that gene product.…”

Section: Discussionmentioning

confidence: 94%

Tissue-specific splicing mutation in acute intermittent porphyria.

Grandchamp

Picat

Mignotte

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

102

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An inherited deficiency of porphobilinogen deaminase [porphobilinogen ammonia-lyase (polymerizing), EC 4.3.1.8] in humans is responsible for the autosomal dominant disease acute intermittent porphyria. Different classes of mutations have been described at the protein level suggesting that this is a heterogeneous disease. It was previously demonstrated that porphobilinogen deaminase is encoded by two distinct mRNA species expressed in a tissue-specific manner. Analysis of the genomic sequences indicated that these two mRNAs are transcribed from two promoters and only differ in their first exon. The first mutation identified in the human porphobilinogen deaminase gene is a single-base substitution (G --A) in the canonical 5' splice donor site of intron 1. This mutation leads to a particular subtype of acute intermittent porphyria characterized by the restriction of the enzymatic defect to nonerythropoietic tissues. Hybridization analysis using oligonucleotide probes after in vitro amplification of genomic DNA offers another possibility of detecting asymptomatic carriers of the mutation in affected families.Acute intermittent porphyria (AIP) is a metabolic disorder characterized by attacks of neurological dysfunction with abdominal pain, hypertension, tachycardia, and peripheral neuropathy. Most attacks are precipitated by drugs, alcohol, caloric deprivation, infections, or endocrine factors (1). AIP results from a partial deficiency of the third enzyme of heme biosynthesis, porphobilinogen deaminase [PBGD; porphobilinogen ammonia-lyase (polymerizing), EC 4.3.1.8] that is inherited as an autosomal dominant trait (1). Early detection of gene carriers is important in the prevention of attacks, as they can be advised to avoid precipitating factors. Since asymptomatic carriers do not consistently excrete abnormal amounts of porphyrins and the porphyrin precursors, 5-aminolevulinic acid and porphobilinogen, the best method for detecting carriers in most AIP families is the determination of erythrocyte PBGD activity (1). There are, however, limitations to this approach as a screening method. Erythrocyte PBGD levels are affected by erythrocyte age and the presence of other diseases (2), and there is some overlap between values for normal individuals and AIP patients (1). In addition, some families have been described with clinical and biochemical criteria indicating AIP, but without the PBGD deficiency in the erythrocytes of the patients (3-5); in fact the distribution of PBGD activity in these AIP patients and their relatives is identical to that in healthy controls (3, 5), in contrast to most AIP families in which erythrocyte PBGD levels show a biphasic distribution. These features point to the existence of a subset of AIP families in whom the mutation is not expressed in erythrocytes.We demonstrated (6) that two isoforms of PBGD, one found in nonerythroid cells and the other found only in erythroid cells, are translated from two mRNAs that differ solely in their 5' termini. These mRNAs are produced through alte...

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“…It should be noted that a previous study (9) demonstrated C3 concentrations between 17 and 58 ng/ml in the sera of three other unrelated caucasoid C3-deficient patients, levels that are below the detection limit of the present assay. However the studies of the gene structure and mRNA expression in our patient suggest (31)(32)(33) in the f3-globin gene, causing fl-thalassaemia; in the phenylalanine hydroxylase gene, causing phenylketonuria (34); and in the porphobilinogen deaminase gene, causing acute intermittent porphyria (35). The effects of naturally occurring mutations in the canonical GT 5' donor splice junction dinucleotide on RNA processing and subsequent protein expression are variable.…”

Section: Resultsmentioning

confidence: 99%

Molecular basis of hereditary C3 deficiency.

Botto

Fong²,

So³

et al. 1990

J. Clin. Invest.

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Hereditary deficiency of complement component C3 in a 10-yr-old boy was studied. C3 could not be detected by RIA of serum from the patient. Segregation of C3 S and C3 F allotypes within the family confirmed the presence of a null gene for C3, for which the patient was homozygous. 30 exons have been characterized, spanning the entire ft chain of C3 and the a chain as far as the C3d region. Sequence analysis of the exons derived from the C3 null gene showed no abnormalities in the coding sequences. A GT-AT mutation at the 5' donor splice site of the intervening sequence 18 was found in the C3 null gene. Exons 17-21 were amplified by the polymerase chain reaction (PCR) from first-strand cDNA synthesized from mRNA obtained from peripheral blood monocytes stimulated with LPS. This revealed a 61-bp deletion in exon 18, resulting from splicing of a cryptic 5' donor splice site in exon 18 with the normal 3' splice site in exon 19. This deletion leads to a disturbance of the reading frame of the mRNA with a stop codon 17 bp downstream from the abnormal splice in exon 18. His parents had both the normal and abnormal C3 mRNA and were shown to be heterozygous for this mutation by sequence analysis of genomic DNA amplified by PCR. Similar splice mutants have previously been reported in the ft-globin, phenylalanine hydroxylase, and porphobilinogen deaminase genes. This mutation is sufficient to cause the deficiency of C3 in the patient.

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Tight linkage between a splicing mutation and a specific DNA haplotype in phenylketonuria

Cited by 217 publications

References 14 publications

Identification of three mutant alleles of the gene for mitochondrial acetoacetyl-coenzyme A thiolase. A complete analysis of two generations of a family with 3-ketothiolase deficiency.

Identification of three mutant alleles of the gene for mitochondrial acetoacetyl-coenzyme A thiolase. A complete analysis of two generations of a family with 3-ketothiolase deficiency.

Tissue-specific splicing mutation in acute intermittent porphyria.

Molecular basis of hereditary C3 deficiency.

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