Unusual molecular findings in Kindler syndrome

Abstract

Kindler syndrome (KS) is a rare inherited skin disorder with blistering and poikiloderma as its main clinical features. It is caused by loss-of-function mutations in the C20orf42 (KIND1) gene which encodes kindlin-1, an actin cytoskeleton-focal contact-associated protein which is predominantly expressed in keratinocytes. We investigated the molecular basis of KS in a 16-year-old Indian boy who had additional clinical findings, including scleroatrophic changes of the hands and feet, pseudoainhum and early onset of squamous cell carcinoma on his foot. Immunostaining for kindlin-1 in the patient's skin was completely absent and sequencing of C20orf42 (KIND1) genomic DNA showed a homozygous splice-site mutation at the -6 position, IVS9-6T-->A. Amplification and sequencing of cDNA from the skin revealed aberrant splicing with either deletion of exon 10 or deletion of exons 9, 10 and 11, both of which involve loss of the pleckstrin homology domain of kindlin-1 that is thought to play a role in cytoskeletal attachment and integrin-mediated cell signalling. Pathogenic splice-site mutations at the -6 position are unusual and have rarely been reported for any genetic disorder. Collectively, these findings extend the spectrum of clinical and molecular abnormalities in this rare genodermatosis.

Mild Clinical Phenotype of Kindler Syndrome Associated with Late Diagnosis and Skin Cancer

“…Environmental factors or disease modifiers must influence the course of the condition, since the position of the mutation does not seem to play a role. Our patients, the oldest reported with FERMT1 mutations to date, seem to be mildly affected as compared to other individuals, since they did not develop complications like pseudo-ainhum, anaemia or severe malignancies [6,7,8]. Life in a temperate climate, and early detection and treatment of premalignant and malignant skin lesions have certainly contributed to the mild course of the disease.…”

“…Cutaneous premalignant and malignant lesions – actinic keratoses, basal cell carcinoma and squamous cell carcinoma – of the sun-exposed areas developed in our patients late, after the age of 50 and 60 years, respectively. To the best of our knowledge, among the more than 100 patients with FERMT1 mutations, 5 were reported to have squamous cell carcinomas (of the lower lip, shoulder, hand and leg) which arose, with one exception, after the fifth decade of life [4,8,10,11,12]. Other patients, in whom the molecular basis of KS has not been established, had squamous cell carcinoma of the hard palate, lower lip, hand and bladder [13,14,15].…”

The kindlin family: functions, signaling properties and implications for human disease

“…A direct consequence of the SC hyperactivation in KS is that patients also have a higher risk of developing skin cancer -mainly squamous cell carcinomas (SCCs) and often at an early age (Arita et al, 2007;Emanuel et al, 2006;Lotem et al, 2001;Mizutani et al, 2012). Although an impaired β1-integrin function has been shown to prevent the formation of skin tumors (Janes and Watt, 2006;Frank et al, 2005), aberrant Wnt and TGFβ signaling caused by loss of kindlin-1 is probably a important reason for the increased risk of tumor development (Beronja et al, 2013;Malanchi et al, 2008;Guasch et al, 2007).…”

Genetic Predisposition to Cutaneous Squamous Cell Carcinoma

“…This gene encodes a protein (kindlin-1) that is involved in linking the actin cytoskeleton with the extra cellular matrix (ECM) and regulating the secretion of various basement membrane factors by the basal keratinocytes. KS unlike other skin related disorders results from defects in the actin-ECM interaction instead of the keratin-ECM interaction (Ashton et al, 2004;Arita et al, 2007). Up to 10% of individuals suffering from KS develop NMSC, mostly cSCC, with the youngest patient reported being a 16 year old boy (Arita et al, 2007;Lai-Cheong et al, 2009;Yazdanfar and Hashemi, 2009).…”

“…KS unlike other skin related disorders results from defects in the actin-ECM interaction instead of the keratin-ECM interaction (Ashton et al, 2004;Arita et al, 2007). Up to 10% of individuals suffering from KS develop NMSC, mostly cSCC, with the youngest patient reported being a 16 year old boy (Arita et al, 2007;Lai-Cheong et al, 2009;Yazdanfar and Hashemi, 2009). Owing to a low incidence of KS (only about 100 cases reported worldwide) a detailed analysis of metastasis and cSCC related death has not been possible.…”