Kindler syndrome: Extension of FERMT1 mutational spectrum and natural history

Abstract

Mutations in the FERMT1 gene (also known as KIND1), encoding the focal adhesion protein kindlin-1, underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with an intriguing progressive phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. Herein we review the clinical and genetic data of 62 patients, and delineate the natural history of the disorder, for example, age at onset of symptoms, or risk of malignancy. Although most mutations are predicted to lead to premature termination of translation, and to loss of kindlin-1 function, significant clinical variability is observed among patients. There is an association of FERMT1 missense and in-frame deletion mutations with milder disease phenotypes, and later onset of complications. Nevertheless, the clinical variability is not fully explained by genotype-phenotype correlations. Environmental factors and yet unidentified modifiers may play a role. Better understanding of the molecular pathogenesis of KS should enable the development of prevention strategies for disease complications.

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

“…Because the clinical symptoms resemble that of other skin-blistering diseases, it is believed that KS is frequently misdiagnosed and the true occurrence of KS is likely to be much higher (Intong and Murrell, 2012). To date, over 73 distinct mutations of the KINDLIN-1 gene have been identified, including deletions of parts or the entire gene, splice-site mutations, nonsense and frame shift mutations, which produce premature termination codons and, consequently, lead to nonsense-mediated mRNA decay and a lack of kindlin-1 protein in epithelial cells (Lai-Cheong et al, 2010;Has et al, 2011). Although the course of the disease varies extensively between patients, it is not possible to correlate the manifestation of specific symptoms or the severity of disease to specific mutations in the KINDLIN-1 gene or additional gene mutations.…”

Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination

“…Recognition of multiple patches in young children is difficult (22), since small normal-appearing areas may only become visible with age, against the progressive poikiloderma (ref. 7 and Supplemental Figure 2).…”

“…KS is characterized by congenital skin blistering and photosensitivity, evolving to poikiloderma with pronounced skin atrophy (7). Poikiloderma refers to a combination of hypo-and hyperpigmentation, atrophy, and telangiectasias and is morphologically characterized by thin epidermis without rete ridges, focal vacuolization of basal keratinocytes, and pigment incontinence.…”

Epidermolysis bullosa in Greece: the patients’ journey so far

“…It has been suggested, that pathogenic missense mutations and in-frame deletions were associated to milder manifestations of the disease and late onset of complications. [35][36][37][38][39][40][41] The four patients with KS in the study presented a common mutation of c.676dupC (exon 5) in the FERMT1/KIND1 gene that results in a frame shift and is predicted to cause a premature termination codon. In the first two patients, the second mutation c.1209C>G mutation causes the formation of a nonsense codon at amino acid residue 403 (p.Tyr403stop); this finding was consistent with the clinical picture of the patients, since they presented a serious disease phenotype.…”