X-linked dominant protoporphyria in a Chinese pedigree reveals a four-based deletion of ALAS2

Background X-linked dominant protoporphyria (XLDPP) is a rare, hereditary disorder that leads to hepatobiliary and hematologic abnormalities including increased erythrocyte protoporphyrin, cutaneous photosensitivity, and decreased iron stores that is caused by a pathogenic mutation of ALAS2 gene. Methods This study aimed to confirm the existence of XLDPP in a Chinese pedigree. We observed and described the dermatoscopic findings of this disorder under dermoscopy, and assessed photo damage in XLDPP patients using the Fotofinder system and very high frequency (VHF) skin ultrasonic system. We performed next generation sequencing and Sanger sequencing to detect and confirm genetic variants in DNA samples from the XLDPP family. Moreover, we monitored the hepatobiliary function as well as hematologic changes in related family members. Results As compared to unaffected control subjects, patients exhibited evidence of severe cutaneous photodamage, causing photoaging, an increase in the size of the gallbladder, increased levels of protoporphyrin in red blood cells, an increase in blood levels of uroporphyrin and hematoporphyrin, and iron deficiency. Conclusions XLDPP was validated by the identification of a four-base-pair deletion (c.1706_1709delAGTG, p.E569fs) in ALAS2 (NM_000032.4) in the proband which segregated with the disease in an X-linked dominant pattern, with hemizygous males being more severely affected than heterozygous females. We also found a missense variant in GATA Binding Protein 1 (GATA1).

[1]  Hongbing Zhang,et al.  X-linked dominant protoporphyria: report of a pedigree and detection of ALAS2 gene mutations , 2016 .

[2]  S. Moriwaki,et al.  X‐linked dominant protoporphyria: The first reported Japanese case , 2016, The Journal of dermatology.

[3]  R. Desnick,et al.  X‐chromosomal inactivation directly influences the phenotypic manifestation of X‐linked protoporphyria , 2016, Clinical genetics.

[4]  C. Lian,et al.  Homozygous ALOXE3 Nonsense Variant Identified in a Patient with Non-Bullous Congenital Ichthyosiform Erythroderma Complicated by Superimposed Bullous Majocchi’s Granuloma: The Consequences of Skin Barrier Dysfunction , 2015, International journal of molecular sciences.

[5]  E. Marchesini,et al.  Long‐term observational study of afamelanotide in 115 patients with erythropoietic protoporphyria , 2015, The British journal of dermatology.

[6]  S. Winter,et al.  Congenital erythropoietic porphyria linked to GATA1‐R216W mutation: challenges for diagnosis , 2015, European journal of haematology.

[7]  Bale,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[8]  H. Bonkovsky,et al.  Loss-of-Function Ferrochelatase and Gain-of-Function Erythroid-Specific 5-Aminolevulinate Synthase Mutations Causing Erythropoietic Protoporphyria and X-Linked Protoporphyria in North American Patients Reveal Novel Mutations and a High Prevalence of X-Linked Protoporphyria , 2013, Molecular Medicine.

[9]  S. Ducamp,et al.  Molecular and functional analysis of the C-terminal region of human erythroid-specific 5-aminolevulinic synthase associated with X-linked dominant protoporphyria (XLDPP). , 2013, Human molecular genetics.

[10]  M. Kacena,et al.  Human phenotypes associated with GATA-1 mutations. , 2008, Gene.

[11]  Joanne,et al.  C-terminal deletions in the ALAS2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload. , 2008, American journal of human genetics.

[12]  D. Steensma,et al.  Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria. , 2007, Blood.

[13]  A. F. Cunha,et al.  An inherited mutation leading to production of only the short isoform of GATA-1 is associated with impaired erythropoiesis , 2006, Nature Genetics.

[14]  R. Desnick,et al.  Uroporphyrinogen III synthase erythroid promoter mutations in adjacent GATA1 and CP2 elements cause congenital erythropoietic porphyria. , 2001, The Journal of clinical investigation.