title: X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria.
abstract: X-linked protoporphyria (XLP), a rare erythropoietic porphyria, results from terminal exon gain-of-function mutations in the ALAS2 gene causing increased ALAS2 activity and markedly increased erythrocyte protoporphyrin levels. Patients present with severe cutaneous photosensitivity and may develop liver dysfunction. XLP was originally reported as X-linked dominant with 100% penetrance in males and females. We characterized 11 heterozygous females from six unrelated XLP families and show markedly varying phenotypic and biochemical heterogeneity, reflecting the degree of X-chromosomal inactivation of the mutant gene. ALAS2 sequencing identified the specific mutation and confirmed heterozygosity among the females. Clinical history, plasma and erythrocyte protoporphyrin levels were determined. Methylation assays of the androgen receptor and zinc-finger MYM type 3 short tandem repeat polymorphisms estimated each heterozygotes X-chromosomal inactivation pattern. Heterozygotes with equal or increased skewing, favoring expression of the wild-type allele had no clinical symptoms and only slightly increased erythrocyte protoporphyrin concentrations and/or frequency of protoporphyrin-containing peripheral blood fluorocytes. When the wild-type allele was preferentially inactivated, heterozygous females manifested the disease phenotype and had both higher erythrocyte protoporphyrin levels and circulating fluorocytes. These findings confirm that the previous dominant classification of XLP is inappropriate and genetically misleading, as the disorder is more appropriately designated XLP.
authors.affiliation: Fondazione IRCCS "Cà-Granda" Ospedale Maggiore Policlinico, U.O. di Medicina Interna, Milano, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Brancaleoni
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Balwani
authors.affiliation: Fondazione IRCCS "Cà-Granda" Ospedale Maggiore Policlinico, U.O. di Medicina Interna, Milano, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Granata
authors.affiliation: Fondazione IRCCS "Cà-Granda" Ospedale Maggiore Policlinico, U.O. di Medicina Interna, Milano, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Graziadei
authors.affiliation: Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milano, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Missineo
authors.affiliation: Fondazione IRCCS "Cà-Granda" Ospedale Maggiore Policlinico, U.O. di Medicina Interna, Milano, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Fiorentino
authors.affiliation: Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milano, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Fustinoni
authors.affiliation: Fondazione IRCCS "Cà-Granda" Ospedale Maggiore Policlinico, U.O. di Medicina Interna, Milano, Italy.|Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milano, Italy.
authors.forename: M D
authors.initials: MD
authors.lastname: Cappellini
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: H
authors.initials: H
authors.lastname: Naik
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Desnick
authors.affiliation: Fondazione IRCCS "Cà-Granda" Ospedale Maggiore Policlinico, U.O. di Medicina Interna, Milano, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Di Pierro
mesh_terms: D000483:Alleles; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D050172:Genes, X-Linked; D040181:Genetic Diseases, X-Linked / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D011166:Porphyrins / Q000378:metabolism; D046351:Protoporphyria, Erythropoietic / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D011524:Protoporphyrins / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics; D049951:X Chromosome Inactivation
chemical_list: D009687:Nuclear Proteins; D011166:Porphyrins; D011524:Protoporphyrins; D011944:Receptors, Androgen; C102796:ZMYM3 protein, human; C028025:protoporphyrin IX
keywords: ALAS2; X-chromosomal inactivation; X-linked protoporphyria; genotype-phenotype