X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria.
X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked protoporphyria.
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DOI：
10.1111/cge.12562
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发表时间：
2016-01
影响因子：
3.5
通讯作者：
Di Pierro E
中科院分区：
文献类型：
--
作者：
Brancaleoni V;Balwani M;Granata F;Graziadei G;Missineo P;Fiorentino V;Fustinoni S;Cappellini MD;Naik H;Desnick RJ;Di Pierro E
X-连锁原卟啉病（XLP）是一种罕见的红细胞生成性卟啉病，由ALAS 2基因的末端外显子功能获得性突变引起ALAS 2活性增加和红细胞原卟啉水平显著增加。患者表现为严重的皮肤光敏性，并可能发生肝功能障碍。XLP最初被报道为X连锁显性，在男性和女性中100%显性。我们的特点是11杂合子女性从6个无关的XLP家庭，表现出显着不同的表型和生化异质性，反映了X染色体失活的突变基因的程度。ALAS 2测序确定了特定的突变，并证实了女性之间的杂合性。测定临床病史、血浆和红细胞原卟啉水平。雄激素受体和锌指MYM 3型短串联重复序列多态性的甲基化测定估计每个杂合子X染色体失活模式。具有相等或增加的偏斜，有利于野生型等位基因表达的杂合子没有临床症状，仅轻微增加红细胞原卟啉浓度和/或含原卟啉的外周血荧光细胞的频率。当野生型等位基因优先失活时，杂合女性表现出疾病表型，并且红细胞原卟啉水平和循环荧光细胞均较高。这些发现证实了先前对XLP的主要分类是不适当的，并且在遗传学上具有误导性，因为这种疾病更适合称为XLP。
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.