Kindler syndrome, an orphan disease of cell/matrix adhesion in the skin – molecular genetics and therapeutic opportunities

ABSTRACT

Introduction: Kindler syndrome (KS) is a complex skin fragility disorder with protean manifestations and considerable morbidity and occasional mortality from cancer development. The characteristic clinical features include blistering, erosions, poikiloderma, atrophy of the skin, photosensitivity and severe involvement of mucous membranes. Ultrastructural findings in the affected skin include tissue cleavage at different, mixed levels at the cutaneous basement membrane zone and reduplication of the dermal-epidermal basement membrane.

Areas covered: The molecular basis of this orphan disease, a subtype of epidermolysis bullosa with autosomal recessive inheritance, has been recently elucidated, and there is increased understanding of the pathomechanistic pathways leading to phenotypic manifestations as a result of mutations in FERMT1. This gene encodes kindlin-1, a multi-functional focal adhesion protein with a role in keratinocyte adhesion and proliferation.

Expert opinion: Information on the genetic basis of this disorder is helpful for confirming the diagnosis with prognostic implications, and it has formed the basis for prenatal testing and preimplantation genetic diagnosis in families at risk for recurrence. Finally, information on the specific mutations and understanding of the pathomechanistic pathways has formed the basis to develop novel allele-specific treatment approaches for this, currently intractable disorder.

KEYWORDS:

• Epidermolysis bullosa
• FERMT1
• kindlin-1
• Kindler syndrome
• treatment of orphan disease

Article highlights

• Kindler syndrome (KS), a subgroup of the epidermolysis bullosa family of skin fragility disorders, is characterized by blistering, erosions, poikiloderma and photosensitivity.

• The most devastating complication of this rare disorder is development of aggressive squamous cell carcinomas with considerable morbidity and mortality.

• KS is caused by biallelic mutations in the FERMT1 gene encoding kindlin-1, a focal adhesion protein involved in regulation of keratinocyte adhesion and proliferation.

• Knowledge of specific mutations and associated perturbations in signaling pathways has provided the basis for development of novel allele-specific treatment approaches.

• A select subgroup of KS patients with specific FERMT1 mutations will benefit from novel drugs facilitating premature termination codon read-through or from chaperone molecules allowing transfer of misfolded kindlin-1 protein to proper subcellular localization.

• These developments will eventually advance management of this, currently intractable disorder.

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Acknowledgments

Carol Kelly assisted with manuscript preparation. During preparation of this review, Dr. Uitto was an External Senior Fellow of the Freiburg Institute for Advanced Studies.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.