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Case Report/Case Series |

Heterozygosity for a Novel Missense Mutation in the ITGB4 Gene Associated With Autosomal Dominant Epidermolysis Bullosa

Iana Turcan, MD1; Anna M. G. Pasmooij, PhD1; Peter C. van den Akker, MD, PhD1,2; Henny Lemmink, PhD2; Gyorgy B. Halmos, MD, PhD3 ; Richard J. Sinke, PhD2; Marcel F. Jonkman, MD, PhD1
[+] Author Affiliations
1Department of Dermatology, Center for Blistering Diseases, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands,
2Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
3 Department of Otorhinolaryngology–Head and Neck Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
JAMA Dermatol. 2016;152(5):558-562. doi:10.1001/jamadermatol.2015.5236.
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ABSTRACT

Importance  Epidermolysis bullosa (EB) is a group of mechanobullous genodermatoses characterized by the fragility of skin and mucous membranes. Mutations in the ITGA6 and ITGB4 genes, encoding the hemidesmosomal protein α6β4-integrin, have been involved in the pathogenesis of EB. To date, the inheritance of these particular genes is known to be exclusively autosomal recessive. Herein, we report a novel heterozygous missense mutation in the ITGB4 gene exerting a dominant negative effect that cosegregates with the EB phenotype in an extended family.

Observations  The clinical phenotype of affected individuals is primarily characterized by nail dystrophy and late onset of mild skin fragility and acral blistering. Some patients developed granulation tissue in the larynx, urethra, lacrimal duct, and external auditory canal. Sequencing the complete set of genes associated with EB revealed a heterozygous missense mutation in exon 5 of ITGB4: c.433G>T, p.Asp145Tyr. The mutation was found in the affected relatives and was not present in unaffected relatives and control DNA samples.

Conclusions and Relevance  This study highlights, for the first time to our knowledge, the possibility of a dominant mode of inheritance for a missense ITGB4 mutation in EB, thus expanding the mutational database and genotype-phenotype correlation for this rare disease.

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Figure 1.
Clinical Pedigree of Family With Autosomal Dominant Epidermolysis Bullosa Due to ITGB4: p.Asp145Tyr Mutation

DNA was obtained from individuals III:2, IV:2, IV:4, V:1, V:2, V:3; m/wt indicates, mutation/wild type, or wt/wt, wild type/wild type underlines the genotype of the particular individual.

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Figure 2.
Clinical Features of Affected Family Members

A, Pachyonychia nail dystrophy consisting of nail thickening, transverse overcurvature, discoloration and brittleness in the index patient (IV-2 in Figure 1); B, Blistering on the sole of the index patient. C, Postoperative circular external auditory canal stenosis, due to granulation tissue formation in the index patient. D, Granulation tissue (arrowhead) in the larynx of his youngest daughter (V-2 in Figure 1).

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Figure 3.
Transmission Electron Microscopy of Nonlesional Skin in the Index Patient

Both normal (black arrowhead) and hypoplastic (red arrowhead) hemidesmosomes in adequate numbers along the epidermal basement membrane zone. The lamina densa displays irregular thickness and some blind off-shoots (asterisk). The intermediate tonofilaments are well inserted and the anchoring fibrils are present. Bar: 0.5 µm.

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Figure 4.
Schematic Representation of the β4-Integrin Subunit, Conservation of Residues and RT-PCR Analysis

A, All known ITGB4 missense mutations involved in epidermolysis bullosa (EB) are indicated above the schematic polypetide with evident clustering within the Von Willebrand factor type A (VWFA) domain. The heterozygous p.Asp145Tyr substitution reported herin is shown in red below the schematic structure. B, Conservation of β4-integrin residue Asp145 (D letter code) between species. C, Alignment of β-integrin subunits sequences shows evident conservation (except β8-integrin) of DDL peptide sequence (boxed area). D, Electrophoresis gel analysis of messenger RNA amplified by nested PCRs in the index patient and his youngest daughter identified no alternatively spliced products in the index patient (IV:2, lane 3) and his youngest daughter (V:2, lane 2), compared with control (lane 1). Bp indicates base pair; COOH, carboxyl; NH2, amino terminus; RT-PCR, real time polymerase chain reaction.

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