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X‐chromosomal inactivation directly influences the phenotypic manifestation of X‐linked protoporphyria
Author(s) -
Brancaleoni V.,
Balwani M.,
Granata F.,
Graziadei G.,
Missineo P.,
Fiorentino V.,
Fustii S.,
Cappellini M.D.,
Naik H.,
Desnick R.J.,
Di Pierro E.
Publication year - 2016
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.12562
Subject(s) - biology , erythropoietic protoporphyria , genetics , heterozygote advantage , allele , penetrance , loss of heterozygosity , protoporphyrin , compound heterozygosity , x inactivation , porphyria , endocrinology , phenotype , x chromosome , microbiology and biotechnology , medicine , gene , biochemistry , porphyrin
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‐chromsomal 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 .