The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal organization are highly heritable. To understand the genetic aetiology of Fuchs endothelial corneal dystrophy (FECD), the most prevalent corneal disorder requiring transplantation, we conducted a genome-wide association study (GWAS) on 1,404 FECD cases and 2,564 controls of European ancestry, followed by replication and meta-analysis, for a total of 2,075 cases and 3,342 controls. We identify three novel loci meeting genome-wide significance ( P <5 × 10 −8 ): KANK4 rs79742895, LAMC1 rs3768617 and LINC00970/ATP1B1 rs1200114. We also observe an overwhelming effect of the established TCF4 locus. Interestingly, we detect differential sex-specific association at LAMC1 , with greater risk in women, and TCF4 , with greater risk in men. Combining GWAS results with biological evidence we expand the knowledge of common FECD loci from one to four, and provide a deeper understanding of the underlying pathogenic basis of FECD.

PURPOSE:In this study, we investigated whether the phenotypic difference observed between two lattice corneal dystrophy type 1 (LCD type 1) cases caused by either a single A546D substitution or an A546D/P551Q double substitution in TGFBIp (transforming growth factor beta induced protein) can be ascribed to (i) a difference in the proteomes of corneal amyloid deposits, (ii) altered proteolysis of TGFBIp, or (iii) structural changes of TGFBIp introduced by the P551Q amino acid substitution.EXPERIMENTAL DESIGN:Amyloid deposits were isolated from the corneas of two siblings with LCD type 1 resulting from A546D/P551Q mutations in the TGFBI gene using laser capture microdissection and subsequently analyzed by LC-MS/MS. Proteolytic processing of TGFBIp was addressed by counting peptide spectra. Lastly, to study the possible effect of the P551Q substitution, recombinant FAS1-4 domain variants were subjected to in vitro stability assays.RESULTS:The amyloid proteomes and TGFBIp processing of the two A546D/P551Q LCD type 1 cases were similar to each other as well as to the A546D amyloid proteome previously reported by us. The stability assays revealed a minor destabilization of the FAS1-4 domain upon the addition of the P551Q mutation, moreover, it resulted in different accessibility to tryptic cleavage sites between the A546D and A546D/P551Q mutant FAS1-4 domain variants.CONCLUSION AND CLINICAL RELEVANCE:The difference in A546D and A546D/P551Q LCD type 1 phenotypes cannot be ascribed to altered corneal amyloid composition or altered in vivo proteolytic processing of TGFBIp. Instead, a small difference in thermodynamic stability introduced by the P551Q mutation most likely causes structural changes of TGFBIp. The MS proteomics data have been deposited to the ProteomeXchange with identifier PXD000307 (http://proteomecentral.proteomexchange.org/dataset/PXD000307).

Amyloidosis is a disease characterized by the formation of extracellular amyloid deposits. Immunoglobulin light-chain amyloidosis can appear as a local disorder presenting with mild symptoms or as a life threatening systemic disease. The systemic form of immunoglobulin light-chain amyloidosis is the most common type of amyloidosis in western countries although it is a rare disease. Identification of the proteins forming amyloid fibrils is essential for the diagnosis of the disease and knowledge about the overall protein composition of the deposits may lead to a larger understanding of the deposition events thereby facilitating a more detailed picture of the molecular pathology. In this pilot study, we investigated the protein composition of amyloid deposits isolated from human specimens of the eyelid, conjunctiva, and orbit. Deposits and internal control tissue (patient tissue without apparent deposits) were procured by laser capture microdissection. Proteins in the captured amyloid and control samples were quantified by liquid chromatography tandem mass spectrometry using the label-free exponential modified Protein Abundance Index (emPAI) method. Immunoglobulin light chain kappa or lambda was found to be the most predominant protein in the amyloid deposits from the eyelid, conjunctiva, and orbit. Five proteins, apolipoprotein A-I, carboxypeptidase B2 (TAFI), complement component C9, fibulin-1 and plasminogen were found solely across all amyloid but not in the control tissue. In addition, the protein profiles identified apolipoprotein E and serum amyloid P component to be associated with the immunoglobulin light chain deposits across all three tissues analyzed. The method used in this study provided high sensitivity and specificity for the type of amyloid and may provide additional information on the pathology of the amyloid deposits in the ocular tissues studied.

PURPOSE:We investigated whether mitochondrial DNA (mtDNA) variants affect the susceptibility of Fuchs endothelial corneal dystrophy (FECD).METHODS:Ten mtDNA variants defining European haplogroups were genotyped in a discovery dataset consisting of 530 cases and 498 controls of European descent from the Duke FECD cohort. Association tests for mtDNA markers and haplogroups were performed using logistic regression models with adjustment of age and sex. Subset analyses included controlling for additional effects of either the TCF4 SNP rs613872 or cigarette smoking. Our replication dataset was derived from the genome-wide association study (GWAS) of the FECD Genetics Consortium, where genotypes for three of 10 mtDNA markers were available. Replication analyses were performed to compare non-Duke cases to all GWAS controls (GWAS1, N = 3200), and to non-Duke controls (GWAS2, N = 3043).RESULTS:The variant A10398G was significantly associated with FECD (odds ratio [OR] = 0.72; 95% confidence interval [CI] = [0.53, 0.98]; P = 0.034), and remains significant after adjusting for smoking status (min P = 0.012). This variant was replicated in GWAS1 (P = 0.019) and GWAS2 (P = 0.036). Haplogroup I was significantly associated with FECD (OR = 0.46; 95% CI = [0.22, 0.97]; P = 0.041) and remains significant after adjusting for the effect of smoking (min P = 0.008) or rs613872 (P = 0.034).CONCLUSIONS:The 10398G allele and Haplogroup I appear to confer significant protective effects for FECD. The effect of A10398G and Haplogroup I to FECD is likely independent of the known TCF4 variant. More data are needed to decipher the interaction between smoking and mtDNA haplogroups.

TGFBIp, also known as keratoepithelin and βig-h3, is among the most abundant proteins in the human cornea, and approximately 60% is associated with the insoluble fraction following extraction in sodium dodecyl sulfate (SDS) sample buffer. TGFBIp is of particular interest because a wide range of mutations causes amyloid or fuchsinophilic crystalloid deposits in the cornea leading to visual impairment. We show that the SDS-insoluble fraction of TGFBIp from porcine and human corneas is covalently linked via a reducible bond to the NC3 domain of type XII collagen in a TGFBIp:type XII collagen stoichiometric ratio of 2:1. Because type XII collagen is anchored to striated collagen fibers of the extracellular matrix, its interaction with TGFBIp is likely to provide anchoring for cells to the extracellular matrix through the integrin binding capability of TGFBIp. Furthermore, the TGFBIp-type XII collagen molecule will affect our understanding of the molecular pathogenesis of the TGFBI-linked corneal dystrophies.

Purpose Fuchs endothelial corneal dystrophy (FECD) is a genetically heterogeneous disorder that has been primarily studied in patients of European or Asian ancestry. Given the sparse literature on African Americans with FECD, we sought to characterize the genetic variation in three known FECD candidate genes in African American patients with FECD. Methods Over an 8-year period, we enrolled 47 African American probands with FECD. All participants were clinically examined with slit-lamp biomicroscopy, and when corneal tissue specimens were available, histopathologic confirmation of the clinical diagnosis was obtained. The coding regions of known FECD susceptibility genes collagen, type VIII, alpha 2 (COL8A2); solute carrier family 4, sodium borate transporter, member 11 (SLC4A11); and zinc finger E-box binding homeobox 1 (ZEB1 [also known as TCF8]) were Sanger sequenced in the 47 probands using DNA isolated from blood samples. Results Twenty-two coding variants were detected across the COL8A2, SLC4A11, and ZEB1 genes; six were nonsynonymous variants. Three novel coding variants were detected: a synonymous variant each in COL8A2 and SLC4A11 and one nonsynonymous variant in ZEB1 (p.P559S), which is predicted to be benign and tolerated, thus making its physiologic consequence uncertain. Conclusions Variation in the COL8A2, SLC4A11, and ZEB1 genes is present in only a small fraction of our African American cases and as such does not appear to significantly contribute to the genetic risk of FECD in African Americans. This observation is on par with findings from previous sequencing studies involving European or Asian ancestry patients with FECD.

Purpose: Specific mutations in the transforming growth factor beta induced (TGFBI) gene are associated with lattice corneal dystrophy (LCD) type 1 and its variants. In this study, we performed an in-depth proteomic analysis of human corneal amyloid deposits associated with the heterozygous A546D mutation in TGFBI.Methods: Corneal amyloid deposits and the surrounding corneal stroma were procured by laser capture microdissection from a patient with an A546D mutation in TGFBI. Proteins in the captured corneal samples and healthy corneal stroma were identified with liquid chromatography-tandem mass spectrometry and quantified by calculating exponentially modified Protein Abundance Index values. Mass spectrometry data were further compared for identifying enriched regions of transforming growth factor beta induced protein (TGFBIp/keratoepithelin/beta ig-h3) and detecting proteolytic cleavage sites in TGFBIp.Results: A C-terminal fragment of TGFBIp containing residues Y571-R588 derived from the fourth fasciclin 1 domain (FAS1-4), serum amyloid P-component, apolipoprotein A-IV, clusterin, and serine protease HtrA1 were significantly enriched in the amyloid deposits compared to the healthy cornea. The proteolytic cleavage sites in TGFBIp from the diseased cornea are in accordance with the activity of serine protease HtrA1. We also identified small amounts of the serine protease kallikrein-14 in the amyloid deposits.Conclusions: Corneal amyloid caused by the A546D mutation in TGFBI involves several proteins associated with other varieties of amyloidosis. The proteomic data suggest that the sequence 571-YHIGDEILVSGGIGALVR-588 contains the amyloid core of the FAS1-4 domain of TGFBIp and point at serine protease HtrA1 as the most likely candidate responsible for the proteolytic processing of amyloidogenic and aggregated TGFBIp, which explains the accumulation of HtrA1 in the amyloid deposits. With relevance to identifying serine proteases, we also found glia-derived nexin (protease-nexin 1) in the amyloid deposits, making this serine protease inhibitor a good candidate for the physiologically relevant inhibitor of one of the amyloid-associated serine proteases in the cornea and probably in other tissues. Noteworthy, the present results are in accordance with our findings from a previous study of corneal amyloid deposits caused by the V624M mutation in TGFBI, suggesting a common mechanism for lattice corneal dystrophies (LCDs) associated with mutations in the TGFBIp FAS1-4 domain.

Different types of granular corneal dystrophy (GCD) and lattice corneal dystrophy (LCD) are associated with mutations in the transforming growth factor beta induced gene (TGFBI). These dystrophies are characterized by the formation of non-amyloid granular deposits (GCDs) and amyloid (LCD type 1 and its variants) in the cornea. Typical corneal non-amyloid deposits from GCD type 2 (R124H), amyloid from a variant of LCD type 1 (V624M) and disease-free tissue controls were procured by laser capture microdissection and analyzed by tandem mass spectrometry. Label-free quantitative comparisons of deposits and controls suggested that the non-amyloid sample (R124H) specifically accumulated transforming growth factor beta induced protein (TGFBIp/keratoepithelin/beta ig-h3), serum amyloid P-component, clusterin, type Ill collagen, keratin 3, and histone H3-like protein. The amyloid (V624M) similarly accumulated serum amyloid P-component and clusterin but also a C-terminal fragment of TGFBIp containing residues Y571 - R588 derived from the fourth fasciclin-1 domain (FAS1-4), apolipoprotein E and apolipoprotein A-IV. Significantly, analyses of the amyloid sample also revealed the presence of the serine protease Htr (High-temperature requirement) A1 and a number of proteolytic cleavage sites in the FAS1-4 domain of TGFBIp. These cleavage sites were consistent with the ligand binding and proteolytic activity of HtrA1 suggesting that it plays a role in the proteolytic processing of the amyloidogenic FAS1-4 domain. Taken together, the data suggest that the amyloidogenic-prone region of the fourth FAS1 domain of TGEBIp encompasses the Y571 - R588 peptide and that HtrA1 is involved in the proteolytic processing of TGEBIp-derived amyloid in vivo. (C) 2011 Elsevier Ltd. All rights reserved.

Fuchs endothelial corneal dystrophy (FECD) is a common, late-onset disorder of the corneal endothelium. Although progress has been made in understanding the genetic basis of FECD by studying large families in which the phenotype is transmitted in an autosomal dominant fashion, a recently reported genome-wide association study identified common alleles at a locus on chromosome 18 near TCF4 which confer susceptibility to FECD. Here, we report the findings of our independent validation study for TCF4 using the largest FECD dataset to date (450 FECD cases and 340 normal controls). Logistic regression with sex as a covariate was performed for three genetic models: dominant (DOM), additive (ADD), and recessive (REC). We found significant association with rs613872, the target marker reported by Baratz et al.(2010), for all three genetic models (DOM: P = 9.33 x 10(-35); ADD: P = 7.48 x 10(-30); REC: P = 5.27 x 10(-6)). To strengthen the association study, we also conducted a genome-wide linkage scan on 64 multiplex families, composed primarily of affected sibling pairs (ASPs), using both parametric and non-parametric two-point and multipoint analyses. The most significant linkage region localizes to chromosome 18 from 69.94cM to 85.29cM, with a peak multipoint HLOD = 2.5 at rs1145315 (75.58cM) under the DOM model, mapping 1.5 Mb proximal to rs613872. In summary, our study presents evidence to support the role of the intronic TCF4 single nucleotide polymorphism rs613872 in late-onset FECD through both association and linkage studies.

Because of the need for a worldwide standardized nomenclature for the corneal dystrophies, an international committee brought together the diverse literature on these disorders and recommended preferred names for each entity.1Weiss J.S. Møller H.U. Lisch W. et al.The IC3D classification of the corneal dystrophies.Cornea. 2008; 27: S1-S83Crossref PubMed Scopus (287) Google Scholar Each corneal dystrophy needs a specific name because all of these entities do not affect the same parts of the cornea or have the same method of inheritance, pathogenesis, prognosis, or treatment. Like many other genetically determined diseases, knowledge about each corneal dystrophy passes through a continuum from clinical discovery, to a clinicopathologic characterization, to chromosomal mapping, to gene identification, and to the detection of mutations. As this knowledge advances over time, some designations gradually fall by the wayside and better terms are proposed based on clinical or clinicopathologic observations or an improved understanding of their cause, pathogenesis, and pathobiologic features.2Weiss J.S. Molecular genetics and the classification of the corneal dystrophies: what next?.Am J Ophthalmol. 2009; 148 ([editorial]): 477-478Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar However, attempts to provide more accurate appropriate appellations often are unsuccessful. After an extended period of use, the names of some diseases become so ingrained in the literature that they are difficult to replace. For example, retinitis pigmentosa is a prime example of a misnomer, because inflammation of the retina (retinitis) is not a feature of this retinopathy. Nevertheless, despite attempts to replace this designation with the more precise name of pigmentary retinopathy, the old name lives on. Even corneal dystrophy is a misnomer because entities embraced under this umbrella do not arise from defective or faulty nutrition, as implied by the word dystrophy derived from the Latin term dystrophia. Particularly for the lay public, this is probably good because changes in nomenclature are not always easy to comprehend. To rename diseases frequently as knowledge advances may provide precision, as hematopathologists have done with the lymphomas, but for those who are not experts in particular diseases, the changes in nomenclature can create an aura of chaos. At anyone point in time, all diseases are not known and new ones come to light, as occurred with the sudden emergence of retinopathy of prematurity, AIDS, and severe acute respiratory syndrome. If a new corneal disease is suspected, it is essential to determine that it has not been described previously. It is also necessary to make sure that the condition is not a variant of a known entity. The age of the patient, the duration of signs and symptoms, as well as the genetic background and other factors influence the phenotypes, sometimes making it difficult or impossible to establish a precise diagnosis on a single patient without additional information about other affected members of the family. As learned from the corneal diseases caused by mutations in the TGFBI gene, distinct clinicopathologic entities are not necessarily independent disorders, but may be fundamentally more similar than suspected.3Klintworth G.K. Corneal dystrophies.Orphanet J Rare Dis. 2009; 4: 7Crossref PubMed Scopus (262) Google Scholar When a new or previously forgotten corneal dystrophy is described, the discoverer has the opportunity to name the new disorder. Others encountering the same entity for the first time may be unaware of an earlier designation and may report their observations under a different term. Thus, the names of an entity may snowball, particularly when one of the original terms does not become established. Of all the conditions that affect the cornea, and indeed the eye, the record number of synonyms belongs to a disorder with multiple names that include chronic actinic keratopathy.4Klintworth G.K. Chronic actinic keratopathy: a condition associated with conjunctival elastosis (pingueculae) and typified by characteristic extracellular concretions.Am J Pathol. 1972; 67: 327-348PubMed Google Scholar Recurrent corneal erosions occur in a variety of distinctly different corneal disorders, including Fuchs, lattice type I, Meesmann, and subepithelial mucinous corneal dystrophies, as well as in other conditions. Sometimes the recurrent erosions have an autosomal dominant method of inheritance and the erosions are the predominant feature of the condition. Albert Franceschetti (1896–1968), the renowned Swiss ophthalmologist, pioneered ophthalmic genetics and, together with 2 colleagues, published a comprehensive 2-volume book, Genetics and Ophthalmology, in 1961.5Waardenburg P.J. Franceschetti A. Klein D. Genetics and Ophthalmology. Blackwell Scientific Publications Ltd, Oxford1961Google Scholar Buried within the first volume of this text is a large 7-generation pedigree of a family with recurrent corneal erosions that he had published previously in 1928.6Franceschetti A. Hereditaere rezidivierende Erosion der Hornhaut.Z Augenheilk. 1928; 66: 309-316Google Scholar The clinical features of affected individuals in this family originally were documented in a rudimentary way, and the Franceschetti paper was cited by Weiss and associates under the broad umbrella of epithelial recurrent erosion dystrophy (ERED).1Weiss J.S. Møller H.U. Lisch W. et al.The IC3D classification of the corneal dystrophies.Cornea. 2008; 27: S1-S83Crossref PubMed Scopus (287) Google Scholar Somewhat similar cases have been named after the geographic location where the corneal dystrophy was discovered, as in the Swedish provinces of Sâmland (Dystrophia Smolandiensis)7Hammar B. Björck E. Lagerstedt K. Dellby A. Fagerholm P. A new corneal disease with recurrent erosive episodes and autosomal dominant inheritance.Acta Ophthalmol Scand. 2008; 86: 758-763Crossref Scopus (21) Google Scholar, 8Hammar B. Lagali N. Ek S. Seregard S. Dellby A. Fagerholm P. Dystrophia Smolandiensis: a novel morphological picture of recurrent corneal erosions.Acta Ophthalmol. 2010; 88: 394-400Crossref PubMed Scopus (17) Google Scholar and Hâlsingland (Dystrophia Helsinglanica).9Hammar B. Björck E. Lind H. Lagerstedt K. Dellby A. Fagerholm P. Dystrophia Helsinglandica: a new type of hereditary corneal recurrent erosions with late subepithelial fibrosis.Acta Ophthalmol. 2009; 87: 659-665Crossref PubMed Scopus (21) Google Scholar, 10Neira W. Hammar B. Hoopainen J.M. et al.Dystrophia Helsinglandica—corneal morphology, topography and sensitivity in a hereditary corneal disease with recurrent erosive episodes.Acta Ophthalmol. 2010; 88: 401-406Crossref PubMed Scopus (4) Google Scholar These variants of ERED share features with relatively minor differences, and it is debatable whether they are indeed independent entities. Rigid geographic boundaries do not encase corneal dystrophies, and designations based on locations are unlikely to withstand the test of time, because the genetic pool of different mutations never remains entirely in a single community. Commonly a new disorder is named after the first person known to describe it, but others are labeled after a subsequent author. The disorder with recurrent corneal erosions that was documented by Franceschetti originally was dubbed hereditary recurrent erosion of the cornea, but it was later also referred to as Franceschetti syndrome II. Eponyms in nomenclature are common, and many eponymous corneal dystrophies are named after ophthalmologists: Ernst Fuchs (1851–1930, Fuchs endothelial corneal dystrophy); Arthur Groenouw (1862–1945, Groenouw corneal dystrophy type 1 and 2, currently known as granular corneal dystrophy and macular corneal dystrophy, respectively); Alois Meesmann (1888–1969, Meesmann corneal dystrophy); Frederick W. Stocker and L. Byerly Holt (Stocker-Holt corneal dystrophy); Max Bücklers (1895–1969, Reis-Bücklers corneal dystrophy); Hans-Jürgen Thiel (Thiel-Behnke corneal dystrophy); Walter F. Schnyder (1892–1980, Schnyder corneal dystrophy); and Hugo Biber (1864–1918), Otto Haab (1850–1931), and Friedrich Dimmer (1855–1926, Biber-Haab-Dimmer corneal dystrophy, currently called lattice corneal dystrophy type 1), and the list goes on and on. At one time diseases, syndromes, and anatomic structures with eponymous names were referred to in the possessive form with an apostrophe, but this practice has fallen into disrepute and the trend of not using the possessive form has gradually gathered momentum in medical writing.11Iverson C. Christiansen S. Flanagin A. et al.JAMA Manual of Style: A Guide for Authors and Editors. Tenth ed. Oxford University Press, Oxford2007: 778-780Google Scholar With countless diseases having eponymous names, many individuals have difficulty learning and remembering the characteristics of the specific disorders, but a skill in recalling them is a distinct advantage for someone interested in trivial pursuit. The human desire to compartmentalize diseases has spawned so-called splitters and lumpers, particularly among individuals studying genetic diseases. Those who are splitters regard each disorder with recurrent epithelial erosions, such as Dystrophia Smolandiensis and Dystrophia Helsinglandica, as distinct entities, but lumpers prefer to group all of these conditions together as variants of ERED. Although differences have been detected between the EREDs, an understanding of the basic defects in each of them remains unknown until the actual mutations in the responsible gene(s) have been identified. Until that time of reckoning, it will not be known whether these conditions are, or are not, variants of the same disease. Publication of this article was Supported by Grants R01EY016514, R011EY012712, and K12 EY016333 from the National Eye Institute, National Institutes of Health, Bethesda, Maryland. The author (G.K.K.) indicates no financial conflict of interest, and is solely responsible for the content of this article.

Hintergrund: Die in jüngster Zeit verfügbaren genetischen Analysen haben die Mängel in der herkömmlichen phänotypischen Methode zur Klassifikation von Hornhautdystrophien (HD) aufgezeigt. Anomalien in verschiedenen Genen können einen einzigen Phänotyp verursachen, wogegen verschiedene Defekte in einem einzigen Gen verschiedene Phänotypen bedingen können. Einige als korneale Dystrophien bezeichnete Störungen scheinen keinen genetischen Hintergrund zu haben. Absicht: Ziel dieser Studie war es, ein neues System zur Klassifizierung der Hornhautdystrophien zu entwickeln, das gleichzeitig aktuelle Daten phänotypischer Beschreibung, pathologischer Untersuchung und Genanalyse miteinbezieht. Methoden: Zur Erstellung einer aktuellen und exakten Nomenklatur wurde das International Committee for Classification of Corneal Dystrophies (IC3D) gegründet. Ergebnisse: Diese anatomische Klassifikation führt die Einordnung der Dystrophien nach den hauptsächlich betroffenen Hornhautschichten fort. Jede Dystrophie besitzt ein Schema aus klinischen, pathomorphologischen und genetischen Informationen. Die Einordnung in die Kategorien 1 – 4 spiegelt den Wissensstand über die jeweilige Dystrophie wider. Die am besten definierten Dystrophien sind in Kategorie 1 zu finden (eine gut definierte Hornhautdystrophie, in der ein Gen entschlüsselt und identifiziert wurde und spezifische Mutationen bekannt sind) und die am wenigsten definierten Dystrophien gehören in Kategorie 4 (eine mögliche Dystrophie, deren klinischer und genetischer Nachweis noch nicht überzeugend erbracht werden konnte). Bei Vorliegen neuer Informationen kann nach einer gewissen Zeit die Nomenklatur überarbeitet werden. Schlussfolgerungen: Die IC 3D-Klassifikation kornealer Dystrophien ist ein neues Klassifizierungssystem, das sowohl viele Aspekte herkömmlicher Definitionen kornealer Dystrophien als auch neue genetische, klinische und histopathologische Informationen berücksichtigt. Die standardisierten Schemata bieten Schlüsselinformationen, die eine Grundlage für das Vorhandensein einer Hornhautdystrophie beinhalten. Das System ist benutzerfreundlich und erweiterbar und kann auf folgender Webseite abgerufen werden: www.corneasociety.org/IC3D (englische Version); online-Datenbank Thieme (deutsche Version). Schlüsselwörter: Hornhautdystrophie (HD), hereditäre korneale Erkrankung, genetische korneale Erkrankung, korneale Histopathologie, Gen, Mutation, Schlüsselreferenz, Eponym, Epitheliale Basalmembran-Dystrophie (EBMD), Epitheliale Rezidivierende Erosionsdystrophie (ERED), Subepitheliale muzinöse Hornhautdystrophie (SMCD), Meesmann-Hornhautdystrophie (MECD), Lisch-epitheliale Hornhautdystrophie (LECD), Gelatinöse tropfenförmige Hornhautdystrophie (GDLD), Grayson-Wilbrandt-Hornhautdystrophie (GWCD), Gittrige Hornhautdystrophie 1 (LCD1), Gittrige Hornhautdystrophie Gelsolin Typ (LCD2), Granuläre Hornhautdystrophie 1 (GCD1), Granuläre Hornhautdystrophie 2 (GCD2), "Avellino" Hornhautdystrophie, Reis-Bücklers-Hornhautdystrophie (RBCD), Thiel-Behnke-Hornhautdystrophie (TBCD), Makuläre Hornhautdystrophie (MCD), Schnyder-Hornhautdystrophie (SCD), Kongenitale stromale-Hornhautdystrophie (CSCD), Fleckchen-Hornhautdystrophie (FCD), Posteriore amorphe Hornhautdystrophie (PACD), Zentral-wolkenfömige Hornhautdystrophie (François) (CCDF), Prae-Descemet-Hornhautdystrophie (PDCD), Fuchs-endotheliale Hornhautdystrophie (FECD), Hintere polymorphe Hornhautdystrophie (PPCD), Kongenitale hereditäre Endotheldystrophie 1 (CHED1), Kongenitale hereditäre Endotheldystrophie 2 (CHED2), X-gebundene Endothel-Hornhautdystrophie (XECD).

Human transforming growth factor β induced protein (TGFBIp) is composed of 683 residues, including an N-terminal cysteine-rich (EMI) domain, four homologous fasciclin domains, and an Arg-Gly-Asp (RGD) motif near the C-terminus. The protein is of interest because mutations in the TGFBI gene encoding TGFBIp lead to corneal dystrophy (CD), a condition where protein aggregates within the cornea compromise transparency. The complete three-dimensional structure of TGFBIp is not yet available, with the exception of a partial X-ray structure of the archetype FAS1 domain derived from Drosophila fasciclin-1. In this study, small-angle X-ray scattering (SAXS) models of intact wild-type (WT) human TGFBIp and a mutant (R124H) are presented. The mutation R124H leads to a variant of granular CD. The deduced structure of the TGFBIp monomer consists of four FAS1 domains in a simple “beads-on-a-string” arrangement, constructed by the superimposition of four consecutive Drosophila fasciclin domains. The SAXS-based model of the TGFBIp R124H mutant displayed no structural differences from WT. Both WT TGFBIp and the R124H mutant formed trimers at higher protein concentrations. The similar association properties and three-dimensional shape of the two proteins suggest that the mutation does not induce any major structural rearrangements, but points towards the role of other corneal-specific factors in the formation of corneal R124H deposits.