Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation.

Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition.

Whole exome sequencing identifies a mutation for a novel form of corneal intraepithelial dyskeratosis.

BACKGROUND: Corneal intraepithelial dyskeratosis is an extremely rare condition. The classical form, affecting Native American Haliwa-Saponi tribe members, is called hereditary benign intraepithelial dyskeratosis (HBID). Herein, we present a new form of corneal intraepithelial dyskeratosis for which we identified the causative gene by using deep sequencing technology. METHODS AND RESULTS: A seven member Caucasian French family with two corneal intraepithelial dyskeratosis affected individuals (6-year-old proband and his mother) was ascertained. The proband presented with bilateral complete corneal opacification and dyskeratosis. Palmoplantar hyperkeratosis and laryngeal dyskeratosis were associated with the phenotype. Histopathology studies of cornea and vocal cord biopsies showed dyskeratotic keratinisation. Quantitative PCR ruled out 4q35 duplication, classically described in HBID cases. Next generation sequencing with mean coverage of 50× using the Illumina Hi Seq and whole exome capture processing was performed. Sequence reads were aligned, and screened for single nucleotide variants and insertion/deletion calls. In-house pipeline filtering analyses and comparisons with available databases were performed. A novel missense mutation M77T was discovered for the gene NLRP1 which maps to chromosome 17p13.2. This was a de novo mutation in the proband's mother, following segregation in the family, and not found in 738 control DNA samples. NLRP1 expression was determined in adult corneal epithelium. The amino acid change was found to destabilise significantly the protein structure. CONCLUSIONS: We describe a new corneal intraepithelial dyskeratosis and how we identified its causative gene. The NLRP1 gene product is implicated in inflammation, autoimmune disorders, and caspase mediated apoptosis. NLRP1 polymorphisms are associated with various diseases.

Amniotic membrane grafting for a case of bilateral giant full-thickness macular hole in Alport syndrome after cataract surgery.

PURPOSE: To describe the surgical management of bilateral giant full-thickness macular hole with sudden onset two months after cataract surgery in a patient with Alport syndrome. METHODS: Observational, single-case report. RESULTS: A 54-year-old female with a history of Alport syndrome presented with severe bilateral visual loss two months after cataract surgery. The diagnosis of bilateral giant full-thickness macular hole was made. We found the absence of the internal limiting membrane and the inability to lift and peel a continuous posterior hyaloid sheet during surgical management with 25-gauge pars plana vitrectomy (left eye). Amniotic membrane grafting followed by gas tamponade were performed for hole closure. The hole remained closed but vision was poorly restored two months after. CONCLUSION: Cataract surgery in patients with Alport syndrome could promote early development of giant full-thickness macular hole. Collagen defects could underlie internal limiting membrane absence and the inability to properly peel the posterior hyaloid.

Correlations of long-term matrix metalloproteinase localization in human corneas after successful laser-assisted in situ keratomileusis with minor complications at the flap margin.

OBJECTIVE: To determine whether matrix metalloproteinases (MMPs) are present long-term in human corneas after successful laser-assisted in situ keratomileusis (LASIK). METHODS: Eighteen postmortem corneas from 10 patients with postoperative intervals of 2 to 8 years after LASIK surgery and 4 normal control corneas from 2 patients were collected from US eye banks and processed for histologic analysis and immunolocalization with antibodies to MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, and MMP-14. RESULTS: Matrix metalloproteinase 7 was present in the epithelium of all corneas. Other MMPs were localized to the wound margin in some post-LASIK corneas. Matrix metalloproteinase 9 was detected around epithelial cells trapped in the lamellar scar in 5 of 6 corneas with epithelial ingrowth. Various MMPs were detected in fibrotic tissue at the wound margin in 2 of 2 corneas with flap retraction. CONCLUSIONS: The presence of MMPs in post-LASIK corneas correlates with an ongoing wound healing process associated with minor post-LASIK complications. Matrix metalloproteinases might contribute to instances of ongoing flap instability, and if so, judicious use of MMP inhibitors could provide benefit.

Correlation between epithelial ingrowth and basement membrane remodeling in human corneas after laser-assisted in situ keratomileusis.

OBJECTIVE: To further investigate the hypothesis that epithelial ingrowth in human corneas after laser-assisted in situ keratomileusis (LASIK) correlates with basement membrane remodeling, as suggested by the presence of matrix metalloproteinase 9 around epithelial cells in the lamellar scar. METHODS: Immunohistochemical analysis and transmission electron microscopy were applied to human postmortem corneas with post-LASIK epithelial ingrowth. RESULTS: Epithelial ingrowth into the flap margin was observed in 8 of 18 corneas (44%). Matrix metalloproteinase 9 immunolocalized around ingrown epithelium in 6 of these 8 corneas (75%). There was a positive correlation between the presence of matrix metalloproteinase 9 at the wound margin and discontinuities in the basement membrane, as determined by laminin and beta(4) integrin immunofluorescence. Transforming growth factor beta2 was present into the stroma of some corneas with epithelial ingrowth and interrupted basement membrane, suggesting some degree of epithelial-stromal interaction. Transmission electron microscopy confirmed large areas of remodeled basement membrane along ingrown epithelial cells. CONCLUSIONS: The neo-basement membrane components underlying the ingrown cells in human corneas with epithelial ingrowth after LASIK appear to be partially disassembled. Epithelial-stromal interaction over time may be related to prolonged wound healing remodeling, which calls into question the stability of the flap.

Esotropias that totally resolve under general anesthesia treated exclusively with bilateral fadenoperation.

PURPOSE: Fadenoperation has been proven to be an efficient method to treat convergence excess because it treats medial rectus (MR) overaction. We wanted to evaluate its efficiency in esotropias that totally disappear under anesthesia, regardless of the amount of deviation in waking hours. METHODS: Included were 122 successive cases of children of ages 3 to 16 years with esotropia that completely disappears under general anesthesia (GA), representing 26.25% of all patients with esotropia that had surgery between August 2002 and July 2004. They all received a fadenoperation (retroequatorial strapping) of both MR without recession with a 5/0 nylon suture. RESULTS: Patients were evaluated between 27 and 51 months postoperatively. Mean initial deviation was 21 prism dioptres (PD) at distance and 31 PD at near fixation. Of the 122 cases, 102 (83.6%) showed stable postoperative deviation between +8 and -8 PD, 7 showed exotropias (< 20 PD), and 13 showed esotropias (< 20 PD). These results were found without correlation to preoperative angle of deviation, ametropia, age at surgery, or association with vertical surgery. CONCLUSION: Our results suggest that fadenoperation of MR is an option to treat esotropias that disappear under anesthesia. The retroequatorial strapping we use seems safer than classical fadenoperation. We believe that the position of the eyes under GA should be considered for the surgical approach of esotropias.