DHPLC mutation analysis of phenylketonuria

Bräutigam, S; Kujat, Annegret; Kirst, Peter; Seidel, Joerg; Lüleyap, H. Ümit; Froster, Ursula G.

doi:10.1016/s1096-7192(02)00228-7

Cited by 16 publications

(10 citation statements)

References 10 publications

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“…The 13 coding exons and the intron-exon boundaries of PAH were amplified by polymerase chain reaction (PCR) using a combination of primers previously published (Br€ autigam et al 2003), and new primers designed using Primer3 software (Rozen and Skaletsky 2000). To reduce the cost of screening, a tiered sequencing approach was adopted, whereby patients were screened first for mutations in exons 7 and 12.…”

Section: Methodsmentioning

confidence: 99%

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

Alexander

Bhattacharya

et al. 2013

JIMD Reports

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Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene. Mutation screening was carried out in a large cohort of PKU patients from New South Wales, Australia. Pathogenic mutations were identified in 99% of the alleles screened, with the two most common mutations (p.R408W and IVS12+1G>A) accounting for 30.7% of alleles. Most individuals were compound heterozygotes for previously reported mutations, but four novel mutations (c. 163+1G>T, c.164-2A>G, c.461A>T [p.Y154F], and c.510-1G>A) and a novel polymorphism (c.60+62C>T) were also identified.A number of patients have been previously tested for their response to dietary supplementation of tetrahydrobiopterin (BH 4 ), the cofactor of PAH. Correlation between genotype and the responses revealed that although genotype is a major determinant of BH 4 responsiveness, patients with the same genotype may also show disparate responses to this treatment. A clinical and biochemical evaluation should be undertaken to determine the effectiveness of PKU treatment by supplementation of BH 4 .

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Section: Methodsmentioning

confidence: 99%

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

Alexander

Bhattacharya

et al. 2013

JIMD Reports

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“…The major cause of missing mutations in a considerable proportion of alleles may be limited sensitivity of the screening method even though DHPLC has been shown to be efficient and effective in analyzing large genes [45][46][47]. Further reasons for failure to detect mutations may be changes residing in regulatory elements or introns distant from the splice donor and acceptor sites that have not been screened, but which may lead to aberrant splicing [32,48,49].…”

Section: Mutation Datamentioning

confidence: 99%

Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD)

Bergmann¹,

Senderek²,

Windelen³

et al. 2005

Kidney International

295

267

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This is the first study that reports the long-term outcome of ARPKD patients with defined PKHD1 mutations. The 1- and 10-year survival rates were 85% and 82%, respectively. Chronic renal failure was first detected at a mean age of 4 years. Actuarial renal survival rates [end point defined as start of dialysis/renal transplantation (RTX) or by death due to end-stage renal disease (ESRD)] were 86% at 5 years, 71% at 10 years, and 42% at 20 years. All but six patients (92%) had a kidney length above or on the 97th centile for age. About 75% of the study population developed systemic hypertension. Sequelae of congenital hepatic fibrosis and portal hypertension developed in 44% of patients and were related with age. Positive correlations could further be demonstrated between renal and hepatobiliary-related morbidity suggesting uniform disease progression rather than organ-specific patterns. PKHD1 mutation analysis revealed 193 mutations (70 novel ones; 77% nonconservative missense mutations). No patient carried two truncating mutations corroborating that one missense mutation is indispensable for survival of newborns. We attempted to set up genotype-phenotype correlations and to categorize missense mutations. In 96% of families we identified at least one mutated PKHD1 allele (overall detection rate 76.6%) indicating that PKHD1 mutation screening is a powerful diagnostic tool in patients suspected with ARPKD.

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“…However, the semiautomated screening DHPLC approach, which was used in five out of six studies, has been frequently shown to be efficient and effective in analyzing large multiexonic genes [Wagner et al, 1999;Rossetti et al, 2002;Brautigam et al, 2003].…”

Section: Patients With Only One or No Identi¢able Pkhd1 Mutationmentioning

confidence: 99%

PKHD1mutations in autosomal recessive polycystic kidney disease (ARPKD)

Bergmann¹,

Senderek²,

Küpper³

et al. 2004

Hum. Mutat.

143

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Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of childhood renal- and liver-related morbidity and mortality. The clinical spectrum is widely variable. About 30 to 50% of affected individuals die in the neonatal period, while others survive into adulthood. ARPKD is caused by mutations in the PKHD1 (polycystic kidney and hepatic disease 1) gene on chromosome 6p12, which is among the largest human genes, with a minimum of 86 exons assembled into a variety of alternatively spliced transcripts. The longest continuous open reading frame is predicted to yield a 4,074-aa (447-kDa) multidomain integral membrane protein (fibrocystin/polyductin) of unknown function. This update compiles all known PKHD1 mutations and polymorphisms/sequence variants. Mutations were found to be scattered throughout the gene without evidence of clustering at specific sites. Most PKHD1 mutations are unique to single families ("private mutations") hampering genotype-phenotype correlations. Correlations have been drawn for the type of mutation rather than for the site of individual mutations. All patients carrying two truncating mutations displayed a severe phenotype with perinatal or neonatal demise, while patients surviving the neonatal period bear at least one missense mutation. However, some missense changes are obviously as devastating as truncating mutations. The present article intends 1) to provide an overview of PKHD1 mutations and polymorphisms/sequence variants identified so far, 2) to discuss potential genotype-phenotype correlations, and 3) to review them in the context of their clinical implications. A constantly updated list of mutations is available online (www.humgen.rwth-aachen.de) and investigators are invited to submit their novel data to this PKHD1 mutation database.

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DHPLC mutation analysis of phenylketonuria

Cited by 16 publications

References 10 publications

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD)

PKHD1mutations in autosomal recessive polycystic kidney disease (ARPKD)

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