Molecular genetics of the cutaneous basement membrane zone. Perspectives on epidermolysis bullosa and other blistering skin diseases.

Uitto, Jouni; Christiano, Angela M.

doi:10.1172/jci115938

Cited by 153 publications

(67 citation statements)

References 36 publications

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“…1 The recessive dystrophic form of epidermolysis bullosa (RDEB) is characterized by severely diminished type VII collagen (col7) production. 2 The homotrimeric col7 protein is synthesized by fibroblasts and keratinocytes and represents the key component of anchoring fibrils that connect cutaneous basement membrane to the dermal matrix. 3 Severe attenuation of anchoring fibrils in RDEB results in impaired dermal-epidermal cohesion and diminished adhesion of gastrointestinal mucosa at the basement membrane zone.…”

Section: Introductionmentioning

confidence: 99%

Amelioration of epidermolysis bullosa by transfer of wild-type bone marrow cells

Tolar

Ishida‐Yamamoto

Riddle

et al. 2009

Blood

151

135

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The recessive dystrophic form of epidermolysis bullosa (RDEB) is a disorder of incurable skin fragility and blistering caused by mutations in the type VII collagen gene (Col7a1). The absence of type VII collagen production leads to the loss of adhesion at the basement membrane zone due to the absence of anchoring fibrils, which are composed of type VII collagen. We report that wild-type, congenic bone marrow cells homed to damaged skin, produced type VII collagen protein and anchoring fibrils, ameliorated skin fragility, and reduced lethality in the murine model of RDEB generated by targeted Col7a1 disruption. These data provide the first evidence that a population of marrow cells can correct the basement membrane zone defect found in mice with RDEB and offer a potentially valuable approach for treatment of human RDEB and other extracellular matrix disorders. IntroductionEpidermolysis bullosa represents a family of severe, lifethreatening skin disorders resulting from mutations in genes encoding protein components of the cutaneous basement membrane zone. Although some forms, such as the junctional type, are lethal in the neonatal period, others, such as the dystrophic forms, lead to years of painful skin blistering and mutilating scarring. The most severe form of dystrophic epidermolysis bullosa (the Hallopeau-Siemens type) is caused by recessive mutations in the type VII collagen gene (Col7A1). 1 The recessive dystrophic form of epidermolysis bullosa (RDEB) is characterized by severely diminished type VII collagen (col7) production. 2 The homotrimeric col7 protein is synthesized by fibroblasts and keratinocytes and represents the key component of anchoring fibrils that connect cutaneous basement membrane to the dermal matrix. 3 Severe attenuation of anchoring fibrils in RDEB results in impaired dermal-epidermal cohesion and diminished adhesion of gastrointestinal mucosa at the basement membrane zone. Compromised integrity of the stratifying squamous epithelia leads to increased cutaneous and mucosal sensitivity to mechanical stress and stigmatizing, and to an eventually lethal, clinical phenotype. Children with RDEB develop painful skin and mucosal blistering, mutilating scarring, alopecia, corneal erosions, tooth decay, esophageal strictures, anemia, joint contractures, small epidermal inclusion cysts (milia), nail dystrophy, and fusion of fingers and toes (pseudosyndactyly or "mitten" deformity) by the age of 6 to 8 years. As a result of extreme skin fragility, aberrant tissue repair, and chronic inflammation, RDEB patients develop squamous cell carcinomas in the third decade of life. 4 At this time, there is no therapeutic intervention with proven curative benefit. Palliative measures include complex bandaging of most of the body surface (to protect the skin from the slightest friction, and to prevent infection and excessive loss of body fluid), surgical debridement and analgesia, and nutritional support (using liquid or pureed food by mouth or via percutaneous gastric feeding tube) and analgesia. Faced wit...

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Section: Introductionmentioning

confidence: 99%

Amelioration of epidermolysis bullosa by transfer of wild-type bone marrow cells

Tolar

Ishida‐Yamamoto

Riddle

et al. 2009

Blood

151

135

View full text Add to dashboard Cite

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“…These features frequently shorten the life span of the affected individuals to two or three decades. Several lines of evidence suggest that the type VII collagen gene (COL7A1) is the candidate gene in RDEB (9). First, electron microscopy of the skin in affected individuals demonstrates altered morphology and scarcity, or even absence of anchoring fibrils, attachment structures extending from the lamina densa of the cutaneous basement membrane zone to the papillary dermis (10 Type VII collagen is a homotrimer composed of three identical polypeptide subunits, known as al (VII) chains ( 19).…”

Section: Introductionmentioning

confidence: 99%

Premature termination codons on both alleles of the type VII collagen gene (COL7A1) in three brothers with recessive dystrophic epidermolysis bullosa.

Christiano¹,

Suga²,

Greenspan³

et al. 1995

J. Clin. Invest.

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Epidermolysis bullosa (EB) is a group of heritable mechano-bullous skin diseases classified into three major categories on the basis of the level of tissue separation within the dermal-epidermal basement membrane zone. In the most severe, dystrophic (scarring) forms of EB, blisters form below the cutaneous basement membrane at the level of the anchoring fibrils, which are composed of type VII collagen. Ultrastructural observations of altered anchoring fibrils and genetic linkage to the type VII collagen locus (COL7A1) have implicated COL7A1 as the candidate gene in the dystrophic forms of EB. We have recently cloned the entire cDNA and the gene for human COL7AL. In this study, we describe distinct mutations in both COL7A1 alleles in three brothers with severe, mutilating recessive dystrophic EB (the Hallopeau-Siemens type, HS-RDEB). The patients are compound heterozygotes for two different mutations, both of which result in a premature termination codon in COL7A1, and the parents were shown to be clinically heterozygous carriers of the respective mutations. Premature termination codons in both alleles of COL7A1 appear to be the underlying cause of severe, recessive dystrophic EB in this family. (J. Clin. Invest. 1995. 95:1328-1334

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“…Furthermore, an abundance of TGF-f in the skin of SSc patients (21,22) and the responsiveness of SSc fibroblasts to stimulation by TGF-3 (23,24) make this growth factor a potential candidate molecule in the pathogenesis of SSc. Type VII collagen consists of three identical a I(VII) chains, each composed of a long collagenous triple-helix flanked by globular amino-and carboxy-terminal noncollagenous domains (25)(26)(27). Type VII collagen is present in human tissues in a restricted distribution, almost exclusively in the basement membrane zone below stratifying squamous epithelia of the skin, mucous membranes, and the cornea of the eye.…”

Section: Introductionmentioning

confidence: 99%

Elevated expression of type VII collagen in the skin of patients with systemic sclerosis. Regulation by transforming growth factor-beta.

Rudnicka¹,

Varga²,

Christiano³

et al. 1994

J. Clin. Invest.

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104

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Molecular genetics of the cutaneous basement membrane zone. Perspectives on epidermolysis bullosa and other blistering skin diseases.

Cited by 153 publications

References 36 publications

Amelioration of epidermolysis bullosa by transfer of wild-type bone marrow cells

Amelioration of epidermolysis bullosa by transfer of wild-type bone marrow cells

Premature termination codons on both alleles of the type VII collagen gene (COL7A1) in three brothers with recessive dystrophic epidermolysis bullosa.

Elevated expression of type VII collagen in the skin of patients with systemic sclerosis. Regulation by transforming growth factor-beta.

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