Novel Ferrochelatase Mutations in Japanese Patients with Erythropoietic Protoporphyria: High Frequency of the Splice Site Modulator IVS3–48C Polymorphism in the Japanese Population

Nakano, Hajime; Nakano, Aoi; Toyomaki, Yuka; Ohashi, Shigeki; Harada, Ken; Moritsugu, Ryuta; Takeda, Hitoshi; Kawada, Akira; Mitsuhashi, Yoshihiko; Hanada, Katsumi

doi:10.1038/sj.jid.5700456

Cited by 29 publications

(28 citation statements)

References 6 publications

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“…In the second family, all three members having symptoms of EPP showed the C 683 →T mutation in combination with the trans IVS3-48C polymorphism. 17 These results from the analysis of two Japanese families indicated that the intronic IVS3-48C polymorphism in the non-mutated allele is a distinct determinant of the EPP phenotype. Their further investigation of the frequency of IVS-48C polymorphism in 104 Japanese controls revealed that the genotypic frequency of IVS3-48C/C was 0.192, that was over 10 times those of European countries (0-0.017).…”

Section: Genetic Characteristics Of Eppmentioning

confidence: 91%

“…17 Pedigree analysis of the other family members showed that the mother and two sisters, all asymptomatic, were heterozygous for this mutation. 17 Restriction fragment polymorphism analysis indicated that the proband was homozygous for the IVS3-48C polymorphism, while other family members, asymptomatic carriers, had a wild-type T at position IVS3-48 in trans to the mutated allele. 17 They concluded that the IVS3-48C polymorphism in one allele and a deleterious mutation (delCAA 853 ) in the other allele caused a phenotype of EPP.…”

Section: Genetic Characteristics Of Eppmentioning

confidence: 99%

“…17 Restriction fragment polymorphism analysis indicated that the proband was homozygous for the IVS3-48C polymorphism, while other family members, asymptomatic carriers, had a wild-type T at position IVS3-48 in trans to the mutated allele. 17 They concluded that the IVS3-48C polymorphism in one allele and a deleterious mutation (delCAA 853 ) in the other allele caused a phenotype of EPP. In the second family, all three members having symptoms of EPP showed the C 683 →T mutation in combination with the trans IVS3-48C polymorphism.…”

Section: Genetic Characteristics Of Eppmentioning

confidence: 99%

Section: Genetic Characteristics Of Eppmentioning

confidence: 99%

“…17 The proband in the first family was heterozygous for a 3-bp deletion from nucleotide positions 853 to 855 in exon 8, designated delCAA 853 . 17 Pedigree analysis of the other family members showed that the mother and two sisters, all asymptomatic, were heterozygous for this mutation. 17 Restriction fragment polymorphism analysis indicated that the proband was homozygous for the IVS3-48C polymorphism, while other family members, asymptomatic carriers, had a wild-type T at position IVS3-48 in trans to the mutated allele.…”

Section: Genetic Characteristics Of Eppmentioning

confidence: 99%

See 4 more Smart Citations

Eryhtropoietic Protoporphyria

Kawada¹,

Kawara²,

Nakano³

2013

Current Genetics in Dermatology

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Section: Genetic Characteristics Of Eppmentioning

confidence: 91%

Section: Genetic Characteristics Of Eppmentioning

confidence: 99%

Section: Genetic Characteristics Of Eppmentioning

confidence: 99%

Section: Genetic Characteristics Of Eppmentioning

confidence: 99%

Section: Genetic Characteristics Of Eppmentioning

confidence: 99%

See 3 more Smart Citations

Eryhtropoietic Protoporphyria

Kawada¹,

Kawara²,

Nakano³

2013

Current Genetics in Dermatology

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Biochemical and molecular diagnosis of erythropoietic protoporphyria in an Ashkenazi Jewish family

Schneider‐Yin

Mamet

Minder

et al. 2008

J of Inher Metab Disea

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Erythropoietic protoporphyria (EPP) is a rare hereditary disorder due to a partial deficiency of ferrochelatase (FECH). The genotype of EPP patients features a mutation on one allele of the FECH gene and a common hypomorphic FECH IVS3-48c on the other allele (M/c). The resulting enzyme activity in patients is ∼35% of that in normal individuals. Ferrochelatase deficiency results in the accumulation of protoporphyrin in the skin, which is responsible for the clinical symptom of cutaneous photosensitivity in patients. In this study, we report the identification of a novel FECH mutation delT23 in an 11-member EPP family of Jewish origin. Two EPP siblings shared an identical genotype of delT23/IVS3-48c (M/c). They were both photosensitive and showed highly increased erythrocyte protoporphyrin. The genotype of the patients' mother, who did not present with any EPP clinical symptoms, was delT23/IVS3-48t (M/t). The patients' father, an offspring of consanguineous parents, was homozygous IVS3-48 c/c. He exhibited a mild photosensitivity, and an increase of 4-fold in erythrocyte protoporphyrin. His FECH mRNA amount was 71% of that of genotype t/t. It is the first reported case of an individual with c/c genotype who exhibits both biochemical and clinical indications of EPP. These results suggest that IVS3-48c is a functional variant of ferrochelatase. The clinical symptoms and biochemical abnormalities in the patients' father could be the result of an interaction between genetic and environmental factors. In addition, the frequency of IVS3-48c in the Ashkenazi Jewish population was estimated at 8%, which is similar to that in the European populations.

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Dominant versus recessive: Molecular mechanisms in metabolic disease

Zschocke

2008

J of Inher Metab Disea

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Inborn errors of metabolism used to be regarded as simple monogenic traits, but a closer look at how different alleles of a gene determine different phenotypes shows that the molecular mechanisms in the individual case are often complicated. Most metabolic disorders represent a spectrum of phenotypes from normal via attenuated to severe (and sometimes prenatally fatal), and disease manifestation is often influenced by other specific genetic or exogenous factors. The terms 'dominant' or 'recessive' relate to the functional consequences of differing alleles in the (compound) heterozygous individual; the terms are irrelevant for homozygous individuals and inappropriate for X-linked disorders. Mutations affecting the same amino acid residue may be associated with different inheritance patterns. True dominant inheritance in metabolism is rare; it may be found e.g. in tightly regulated biosynthetic pathways or when minor changes in metabolite concentrations have a functional effect. Some disorders such as erythropoietic protoporphyria show pseudodominant inheritance due to prevalent loss-of-function polymorphisms in the general population and are better acknowledged as recessive traits. The term 'variable expressivity' is not helpful with regard to autosomal recessive disorders when variable phenotypes are explained by different mutations in the respective gene. Clonal unmasking of a heterozygous mutation through somatic loss of the second allele, the main pathomechanism in inherited tumour predisposition syndromes, is rare in metabolic disorders, but focal congenital hyperinsulinism is a notable exception. Somatic mosaicism for an OTC gene mutation is given as an example of an apparently heterozygous mutation pattern in a boy with an X-linked disease.

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Novel Ferrochelatase Mutations in Japanese Patients with Erythropoietic Protoporphyria: High Frequency of the Splice Site Modulator IVS3–48C Polymorphism in the Japanese Population

Cited by 29 publications

References 6 publications

Eryhtropoietic Protoporphyria

Eryhtropoietic Protoporphyria

Biochemical and molecular diagnosis of erythropoietic protoporphyria in an Ashkenazi Jewish family

Dominant versus recessive: Molecular mechanisms in metabolic disease

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