title: Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R.
abstract: Hereditary coproporphyria (HCP) is an autosomal dominant acute hepatic porphyria due to the half-normal activity of the heme biosynthetic enzyme, coproporphyrinogen oxidase (CPOX). The enzyme catalyzes the step-wise oxidative decarboxylation of the heme precursor, coproporphyrinogen III, to protoporphyrinogen IX via a tricarboxylic intermediate, harderoporphyrinogen. In autosomal dominant HCP, the deficient enzymatic activity results primarily in the accumulation of coproporphyrin III. To date, only a few homozygous HCP patients have been described, most having Harderoporphyria, a rare variant due to specific CPOX mutations that alter enzyme residues D400-K404, most patients described to date having at least one K404E allele. Here, we describe a Turkish male infant, the product of a consanguineous union, who presented with the Harderoporphyria phenotype including neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. He was homoallelic for the CPOX missense mutation, c.980A>G (p.H327R), and had massively increased urinary uroporphyrins I and III (9,250 and 2,910 μM, respectively) and coproporphyrins I and III (895 and 19,400 μM, respectively). The patient expired at 5 months of age from an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site, thereby accounting for the Harderoporphyria phenotype.
authors.affiliation: Department of Pediatric Metabolism and Nutrition, Gazi University Hospital, Ankara, Turkey.
authors.forename: Alev
authors.initials: A
authors.lastname: Hasanoglu
authors.forename: Manisha
authors.initials: M
authors.lastname: Balwani
authors.forename: Ciğdem S
authors.initials: CS
authors.lastname: Kasapkara
authors.forename: Fatih S
authors.initials: FS
authors.lastname: Ezgü
authors.forename: Ilyas
authors.initials: I
authors.lastname: Okur
authors.forename: Leyla
authors.initials: L
authors.lastname: Tümer
authors.forename: Alpay
authors.initials: A
authors.lastname: Cakmak
authors.forename: Irina
authors.initials: I
authors.lastname: Nazarenko
authors.forename: Chunli
authors.initials: C
authors.lastname: Yu
authors.forename: Sonia
authors.initials: S
authors.lastname: Clavero
authors.forename: David F
authors.initials: DF
authors.lastname: Bishop
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D003241:Consanguinity; D046349:Coproporphyria, Hereditary / Q000175:diagnosis* / Q000235:genetics*; D003304:Coproporphyrinogen Oxidase / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D011165:Porphyrinogens / Q000235:genetics / Q000378:metabolism*
chemical_list: D011165:Porphyrinogens; C018563:harderoporphyrinogen; D003304:Coproporphyrinogen Oxidase