A homozygous nonsense mutation within the dystonin gene coding for the coiled-coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive epidermolysis bullosa simplex.
Epidermolysis bullosa (EB) is a group of autosomal dominant and recessive blistering skin diseases in which pathogenic mutations have been reported in 13 different genes encoding structural proteins involved in keratinocyte integrity, as well as cell-matrix or cell-cell adhesion. We now report an inherited skin fragility disorder with a homozygous nonsense mutation in the dystonin gene (DST) that encodes the coiled-coil domain of the epithelial isoform of bullous pemphigoid antigen 1, BPAG1-e (also known as BP230). The mutation, p.Gln1124X, leads to the loss of hemidesmosomal inner plaques and a complete absence of skin immunostaining for BPAG1-e, as well as reduced labeling for plectin, the beta4 integrin subunit, and for type XVII collagen. The 38-year-old affected individual has lifelong generalized trauma-induced spontaneous blisters and erosions, particularly around the ankles. In addition, he experiences episodic numbness in his limbs, which started at the age of 37 years. These neurological symptoms may also be due to DST gene mutation, although he has a concomitant diagnosis of CADASIL (cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy), a cerebral small-vessel arteriopathy, which thus complicates the genotype-phenotype interpretation. With regard to skin blistering, the clinicopathological findings expand the molecular basis of EB by identifying BPAG1-e pathology in a new form of autosomal recessive EB simplex.
Groves
Richard W
RW
St John's Institute of Dermatology, The Guy's and St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, UK.
Liu
Lu
L
Dopping-Hepenstal
Patricia J
PJ
Markus
Hugh S
HS
Lovell
Patricia A
PA
Ozoemena
Linda
L
Lai-Cheong
Joey E
JE
Gawler
Jeffrey
J
Owaribe
Katsushi
K
Hashimoto
Takashi
T
Mellerio
Jemima E
JE
Mee
John B
JB
McGrath
John A
JA
D000328:Adult; D001768:Blister / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018389:Codon, Nonsense / Q000235:genetics*; D024143:Collagen Type VII / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D000071821:Dystonin; D016110:Epidermolysis Bullosa Simplex / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D022002:Hemidesmosomes / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D039663:Integrin beta4 / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D051190:Plectin / Q000378:metabolism; D020033:Protein Isoforms; D012867:Skin / Q000378:metabolism
D002352:Carrier Proteins; D018389:Codon, Nonsense; D024143:Collagen Type VII; D003598:Cytoskeletal Proteins; C486268:DST protein, human; D000071821:Dystonin; D039663:Integrin beta4; D009419:Nerve Tissue Proteins; D051190:Plectin; D020033:Protein Isoforms