Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008

WDR36 and Myocilin?

Hauser et al. have recently screened a total of 118 JOAG and POAG patients and identified 32 WDR36 sequence variations (146). The authors reported that although the observed WDR36 variants did not consistently segregate with the glaucoma phenotype in all the affected individuals of their pedigrees, those who carried a WDR36 mutation in addition to a MYOC mutation presented with a more severe phenotype. In their study, the WDR36 disease-susceptibility variants of L25P and D658G were also found in two JOAG families with previously identified MYOC mutations of T377M and Q368X, respectively. Therefore, Hauser et al. suggested that WDR36 might be a glaucoma-modifier gene. In this study, one pedigree showed compound WDR36-L25P/MYOC-T377M variation in three out of the four affected sibs. Likewise, in another family with only two affected subjects, only one had the compound WDR36-D658G/MYOC-Q368X variation. In both of these families, the two founding parents were deceased and their JOAG phenotypes were unknown. It is possible that one parent was normal and contributed the WDR36 polymorphic allele of L25P or D658G while the other parent was affected with JOAG and contributed the MYOC mutation of T377M or Q368X. We have recently screened a total of 19 JOAG (n = 7) and POAG (n = 12) familial and sporadic cases with known MYOC mutations for presence of WDR36 variations. Only one JOAG case showed a new mutation, but the affected individuals with or without this WDR36 mutation did not show any clinical diversity with respect to their age of onset, disease severity, or response to medical or surgical treatments. We concluded that affected members of this family with only MYOC mutation alone and/or with compound mutations in WDR36 and MYOC genes do not show any obvious clinical differences. Therefore, further studies are needed to confirm or to refute such association between WDR36 and MYOC mutations and their potential modifying effects on the clinical presentation of glaucoma.

WDR36 Protein Structure

The WDR36 (GenBank accession no. NM_139281) transcript is 6592-bp long, contains 23 exons, and encodes for 951 amino acids. As yet, no differentially spliced forms of this gene have been reported though one cDNA clone (AL832494) in the public domain is missing the two exons of 2 and 21, which is anticipated to encode for a putative protein that is only 383 amino acids long. The WDR36encoded protein consists of at least seven known motifs: a Guanine nucleotide-binding protein or (G)-beta WD-40 repeat, an AMP-dependent synthesize and ligase, a minichromosome maintenance-5 (MCM-5), a cytochrome cd1-nitrite reductase-like (C- terminal heme d1), a lethal giant larvae homolog 2 (LLGL2), an Utp21-specific WD40 associated putative domain, a Quinoprotein amine dehydrogenase, and beta chain-like (Qamine_DH_B_like). WDR36 also has been identified as one of the proteins that is uniquely involved in T-cell activation, and it is reported to be highly co-regulated with interleukin 2 (IL2). This gene encodes for a T-cell activation protein with a minimum of eight WD40 repeats (148), and therefore, it is also recognized as T-cell activation WD repeat protein (TA-WDRP).

WDR36 Gene Expression

As WDR36 is a novel gene and in silico information on this gene is very limited, as a first step in determining its role in glaucoma pathogenesis, expression of this gene was studied in different human ocular and non-ocular tissues by northern blotting and RT–PCR (23). Using northern blotting, two distinct mRNA transcripts of 5.9 kb and 2.5 kb were observed in human heart, placenta, liver, skeletal muscle, kidney, and pancreas. In mice, two transcripts of 3.5 kb and 2.9 kb showed analogous expression patterns to humans. However, it is not clear at this point whether these two transcripts were produced by alternative splicing or by the use of two different promoters. Using RT–PCR, the expression of WDR36 and its homolog, Wdr36, was studied in humans and mice, respectively. WDR36 gene expression was established in human ocular tissues, including the lens, iris, sclera, ciliary muscles, ciliary body, TM, retina, and optic nerve, which further support its role in the etiology of glaucoma. The mRNA expressions of this gene were detected in 7-, 11-, 15-, and 17-day-old developing mouse embryos, thus indicating the early presence of this gene during the embryonic mouse development. As very similar mRNA expression patterns have also been observed for the CYP1B1 gene, it is reasonable to postulate that WDR36-like CYP1B1 may equally be involved in the early stages of eye development.

WDR36 and Glaucoma

The molecular mechanism of WDR36 in the pathogenesis of different forms of glaucoma is still unclear. However, based on the data provided by different investigators, WDR36 is now emerging as an important contributor in development of the glaucoma phenotype. Discovery of WDR36 gene mutations in a group of POAG subjects and its potential involvement in T-cell activation is in direct agreement with previous studies that suggested T-cell-mediated immunity has a fundamental function in glaucoma pathways. For example, in 2004, Schwartz demonstrated effective T-cell- based neuroprotection in rats that were vaccinated with Cop-1 (149). In 2005, Bakalash et al. conducted a study that showed the protective effect of Cop-1 against RGC death, which was caused by the increase in IOP only in the presence of T-cell function (150). In another study, Yang et al. suggested that T-lymphocyte and soluble IL-2 receptor levels are significantly changed in the glaucoma patients (151). The evidence from such studies suggests a need for further investigation into molecular mechanism of WDR36 and the way that this gene and its protein products participate in the development of POAG. Such studies may in turn open new avenues for better understanding of glaucoma pathogenesis as it may further help to slow-down or stop this blinding condition before it is fully developed into a silent optic neuropathy.

After identification of the WDR36 gene at the GLC1G locus, two recent studies presented evidence for the existence of other glaucoma-related loci within the immediate vicinity of the GLC1G locus. The first study used a large JOAG family from the Ibanez region of the Philippines and mapped a new locus to 5q22.1-q32 and within a region of approximately 36-Mb interval (152) that is immediately below the GLC1G locus (see Fig. 2). The JOAG phenotype in this family is not caused by the WDR36 gene mutations. The second study used a group of type 2 diabetes subjects with documented increased IOP from the West African population (153) and

showed evidence for an IOP locus on 5q22 that is overlapping with the GLC1G locus (see Fig. 2). However, it is not clear as of this writing whether the families linked to this IOP locus will have any mutations in the WDR36 gene. If so, such observation may suggest that the WDR36 gene mutations may additionally be involved in the regulation or control of IOP levels, at least, in this West African population. It is noteworthy that such studies not only validate the importance of the 5q region in different subtypes of glaucoma and with diverse ethnical backgrounds but also raise the possibility that another glaucoma-related gene may exist within the close proximity of the GLC1G/WDR36 locus.

Clinical Screening for Gene Mutations

Although discovery of the WDR36 gene does not directly alter our perception, understanding, or our immediate clinical management of the glaucoma patients at this point, this gene can be used to help many familial and sporadic cases. Individual subjects with prior family history of glaucoma have a 50% risk of inheriting the mutated gene, as POAG is transmitted in an autosomal-dominant fashion. However, this gene-specific risk is further modified and partially dependent on incomplete penetrance rate (i.e., elderly subjects with known gene mutation but with no sign of glaucoma). A number of clinical and molecular studies have estimated the POAG incomplete penetrance rate as being 85–90%. Therefore, once an affected subject in a given glaucoma family is identified as having a specific WDR36 gene mutation, that information can be rapidly used to test and to determine whether the other affected or normal subjects of the same family also carry the same mutation. If it is determined that a normal and asymptomatic subject has the same mutation, the genetic risk of that person developing glaucoma suddenly increases from a 50% family-based risk to close to 100%, depending on future determination of incomplete penetrance rate for the WDR36 gene. For sporadic cases, the presence of a specific WDR36 mutation will increase the risk from an age-dependent population risk to approximately 100% and again, this risk is subjected and modified further by the rate of incomplete penetrance for the gene. The other direct clinical utility of WDR36 gene mutations in patient management will become available within the next few years when a large number of POAG patients are screened and an accurate genotype–phenotype correction is established for this gene. For example, for OPTN, it is already determined that subjects with E50K mutation are more severely affected and require an earlier medical and surgical intervention to control their disease progression as compared to other affected subjects without this specific gene mutation. Comparable clinical interventional steps have also been suggested by similar genotype–phenotype correction studies for other two glaucoma-causing genes of CYP1B1 and MYOC. Therefore, through careful planning and coordination with a molecular diagnostic laboratory, it is possible to determine and significantly alter the clinical management of glaucoma subjects with a given disease-causing mutation in one of the CYP1B1, MYOC, OPTN, or WDR36 genes. On rare occasions and in large families with multiply affected subjects in different branches and generations, in which its genetic linkage is well-established to a given chromosomal location, it is equally possible to significantly alter the genetic risk of an asymptomatic subject even if the defective gene in that

family is not identified as yet. Molecular geneticists and genetic counselors will be able to provide such risk assessment to the interested family members.

SUMMARIES AND CONCLUSION

Over the last decade, an extensive effort has been made to map and clone various glaucoma genes. Although over 20 glaucoma loci have been mapped, only four of their defective genes have been identified so far: cytochrome P450 1B1 (CYP1B1) for PCG, MYOC for JOAG, optineurin (OPTN) for normal-pressure glaucoma (NPG), and WD40 repeat domain 36 (WDR36) for adult-onset POAG (POAG).

The CYP1B1 gene is involved in the etiology of a significant percentage of familial (>80%) and sporadic (>30%) cases of PCG, as well as in subjects affected with Peter’s anomaly, Rieger’s anomaly, JOAG, and POAG. The Cyp1b1 knockout mouse shows a very similar phenotype to PCG. Extensive in vitro and in vivo analyses of this gene have shed some light on functional, biological, and biochemical properties of this enzyme. Future work will include understanding the functional consequence of CYP1B1 mutations leading to incomplete penetrance, the role of CYP1B1 in the etiology of JOAG, POAG, and possibly other glaucoma subtypes, and identification of eye-specific substrates metabolized by this enzyme that play a direct role in the development of PCG and other ocular conditions.

The OPTN gene is mutated mainly in familial cases of NTG, and although mutations in this gene are also reported in JOAG cases, it seemingly plays a small part in the etiology of POAG. The importance of this gene is multifold. First, this is the first and the only gene so far detected that is involved in the NTG phenotype. Second, a specific transgenic mouse for the common OPTN-E50K mutation showed a molecular defect in the optic nerve region that closely resembles the NTG phenotype in man. This is the first animal model for an adult-onset glaucoma gene. Third, the OPTN protein interacts with many interesting proteins and so far at least eight of its partners have been reported although more recently we also identified additional putative-interacting partners for this protein. The interactions of OPTN with these proteins have provided new understanding for participation of this protein in multidimensional complexes that is involved in a number of neurodegenerative diseases. The OPTN protein–protein interaction field is moving rapidly, and it is anticipated that significant data will be generated from such studies on the role of OPTN in ocular development as well as on its role in other protein complexes.

The WDR36 is the most recently identified gene for adult-onset POAG, and therefore, very little is yet known about its biological function and even its overall role and significance in POAG and possibly other ocular conditions. The limited data that are available from four different populations suggest that WDR36 mutations might be involved in between 10% and 17% of glaucoma cases. However, this estimate is premature and requires additional confirmation by many other investigators around the world. The suggestion that WDR36 may act as a modifier for the MYOC gene product by enhancing the clinical severity of patients with mutations in both of these genes has not been duplicated by our recent study of this gene in a group of glaucoma subjects with known mutations in the MYOC gene. Current studies are underway to

fully characterize the protein product of the gene and to study its role and function in eye development.

Although the field of molecular genetics of glaucoma has been relatively successful in identifying the chromosomal location of 24 different glaucoma loci, the lack of genetic linkage in many other families suggests that perhaps another 25–50 glaucoma loci have yet to be identified. Therefore, it is possible that the human genome contains between 50 and 75 glaucoma-causing genes. Given the current rate, in which over the last 10 years only four such glaucoma-causing genes have been identified and partially characterized, it may be a long time before the remaining anticipated glaucoma loci can be mapped and their defective genes are identified. Experience from previous non- ocular-cloned genes further suggests that it will be probably on average 10–15 years before the function of a single defective gene can be fully realized. Therefore, one must conclude that the genetics field of glaucoma is still very young, and a significant degree of collaborative work is needed before our understanding of the molecular complexity of glaucoma can be fully appreciated. It is only then, that one may use such knowledge efficiently to develop appropriate clinical treatment and possibly genetic intervention at the cellular level to cure glaucoma in the affected subjects. However, although direct molecular intervention may not be readily available to the affected patients as yet, their immediate family members can be significantly benefited by currently available molecular diagnosis, prenatal, and presymptomatic diagnosis and by use of genotype–phenotype correlations (type of gene mutation and their observed clinical parameters) that are already established for a number of the known glaucoma genes. It is anticipated that discovery of additional glaucoma-causing genes will make a significant contribution to the clinical management of glaucoma sufferers in the not too distant future.

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