The Kindler Syndrome: A Spectrum of FERMT1 Mutations in Iranian Families

Youssefian, Leila; Vahidnezhad, Hassan; Barzegar, Mohammadreza; Li, Qiaoli; Sotoudeh, Soheila; Yazdanfar, Ameneh; Ehsani, Amir Hooshang; Kajbafzadeh, Abdol‐Mohammad; Mozafari, Nikoo; Daryani, Nasser Ebrahimi; Agha‐Hosseini, Farzaneh; Zeinali, Sirous; Uitto, Jouni

doi:10.1038/jid.2015.9

Cited by 32 publications

(36 citation statements)

References 17 publications

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“…5 Kindler syndrome is a rare subtype of epidermolysis bullosa and is due to biallelic mutations in the fermitin family member 1 (FERMT1) gene. 10 It commonly presents with blisters on the dorsum of the hands and feet following trauma or sun exposure, similar to our patient's presentation, but is not associated with pink urine. 10 Congenital erythropoietic porphyria is a rare genetic disorder that causes photodistributed blistering.…”

Section: A S E Pr E S E Ntati O Nsupporting

confidence: 79%

Progressive blistering and hypertrichosis in a young child

Chen

Kuemmet

Chiu

2019

Pediatric Dermatology

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Section: A S E Pr E S E Ntati O Nsupporting

confidence: 79%

Progressive blistering and hypertrichosis in a young child

Chen

Kuemmet

Chiu

2019

Pediatric Dermatology

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“…S14A). Five missense mutations in kindlins have been reported (41)(42)(43)(44). By fitting them in the kindlin2 structure, we analyzed potential effects on protein folding or target binding due to these mutations (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

Structural basis of kindlin-mediated integrin recognition and activation

Deng

Sun

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

142

182

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Kindlins and talins are integrin-binding proteins that are critically involved in integrin activation, an essential process for many fundamental cellular activities including cell-matrix adhesion, migration, and proliferation. As FERM-domain-containing proteins, talins and kindlins, respectively, bind different regions of β-integrin cytoplasmic tails. However, compared with the extensively studied talin, little is known about how kindlins specifically interact with integrins and synergistically enhance their activation by talins. Here, we determined crystal structures of kindlin2 in the apo-form and the β1-and β3-integrin bound forms. The apo-structure shows an overall architecture distinct from talins. The complex structures reveal a unique integrin recognition mode of kindlins, which combines two binding motifs to provide specificity that is essential for integrin activation and signaling. Strikingly, our structures uncover an unexpected dimer formation of kindlins. Interrupting dimer formation impairs kindlin-mediated integrin activation. Collectively, the structural, biochemical, and cellular results provide mechanistic explanations that account for the effects of kindlins on integrin activation as well as for how kindlin mutations found in patients with Kindler syndrome and leukocyte-adhesion deficiency may impact integrin-mediated processes.I ntegrins, composed of α-and β-subunits, are the major receptors mediating the cell-extracellular matrix (ECM) adhesion (1-3). By connecting specific ECM proteins and diverse cytoskeletal regulators, integrins mediate bidirectional transmembrane signaling (4, 5). Stable integrin-ECM interaction and subsequent signaling require integrin activation, which was reported to be mediated by talin, a 4.1-protein/ezrin/radixin/moesin (FERM) domain-containing protein (6). Recently, kindlins, another family of FERM-containing proteins, were found to play crucial roles in integrin activation and signaling (7-12).The kindlin family consists of three members in vertebrates, kindlin1/2/3, each containing a FERM domain and a PH domain (Fig. 1A) (13). Compared with the typical FERM domain that consists of three lobes (F1, F2, and F3), kindlin-FERM contains an additional N-terminal F0 lobe. In kindlins, the F1 and F2 lobes are split by a largely unstructured insertion and the PH domain, respectively (Fig. 1A). Kindlins, although sharing high sequence similarity (SI Appendix, Fig. S1), show distinct tissue distributions and nonredundant functions. Kindlin1 is expressed mainly in epithelia, and nonfunctional kindlin1 mutations lead to Kindler syndrome, a congenital skin disease (14-16). Expression of kindlin3 is restricted to the hematopoietic system, and mutations in kindlin3 were found to associate with leukocyte-adhesion deficiency type III (LADIII) (17, 18). Kindlin2 is ubiquitously expressed, and loss of kindlin2 in mice leads to peri-implantation lethality (11). Kindlins are also involved in tumorigenesis and metastasis (19). The kindlin-associated diseases are due, at least in part...

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“…This is due to three factors: (i) the KS phenotype may overlap with those of other EB types; (ii) specific antibodies to kindlin-1 are not widely available and display faint immunostaining signals, even in normal human skin, probably because of the discrete distribution of "focal adhesion" equivalents in the tissue; and (iii) the broad spectrum of mostly private FERMT1 mutations and mutational mechanisms (HGMD professional 2015.1, https://gre nada.lumc.nl/LOVD2/) (Fuchs-Telem et al, 2014;Youssefian et al, 2015). Because of the long-term severe complications of KS, in particular aggressive squamous cell carcinomas, periodontitis, (a) Erosions were present at birth and skin atrophy at the age of 1.5 years in case 1.…”

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confidence: 99%